JP2021525595A - Thin multidrug injection system and method - Google Patents

Abstract

A thin fluid infusion system and method for injecting fluid into a tumor in the body, comprising an extension member, a plurality of fluid delivery members, and a plurality of fluid reservoirs. Each of the fluid reservoirs is fluidly coupled to a single fluid delivery lumen of a single fluid delivery member such that the fluid delivery member is fluidly independent of all other fluid delivery members. Can be done. Multiple fluid delivery members may be configured to exit the distal end of the extension member and extend into the tumor when the system is positioned within the patient's body. A fluid delivery mechanism can be operably coupled to multiple fluid reservoirs for delivering fluid from multiple fluid reservoirs to multiple fluid delivery members and injecting the fluid into the tumor.

Description

(Cross reference)
The present application claims the benefit of US Provisional Application No. 62 / 679,589 filed June 1, 2018, which is incorporated herein by reference in its entirety for any purpose.

(background)
A fundamental problem in anticancer drug development is that antitumor efficacy in preclinical cancer models may not translate into efficacy in patients or patient outcomes. In many cases, the drug can be tested in a preclinical in vitro or in vivo system that cannot accurately represent the clinical disease. In vitro cell culture-based systems often provide static and homogeneous test conditions, for example, in which the effects of altering tumor microenvironmental conditions or cell heterogeneity cannot be considered, for example. In vivo animal model-based systems can provide clinics with slightly better transformations, but they often differ in tumor microenvironment (especially genes, molecules, etc.) compared to clinical human tumors. Immunity, and cellular differences), various growth conditions, and various other factors interfere with their predictive usefulness.

(wrap up)
Therefore, it would be desirable to provide improved methods, systems, and devices for drug candidate testing for efficacy in clinical tumors. A proposed embodiment of such a system is one or more drug candidates to discrete mapped locations of clinical tumors for simultaneous assessment of drug candidates in a growing tumor of a biological subject. In-situ injection can be provided. The effect of the drug can be observed as a spatially defined tumor response following excision or biopsy of the injected tumor tissue. Thus, the efficacy of multiple drug candidates can be assessed directly in the clinical setting, which can lead to improved predictions of the therapeutic response to systemic drug delivery.

Furthermore, it would be desirable if improved methods, systems, and devices for drug candidate testing could reach the subcutaneous tumor in a minimally invasive manner. The proposed embodiments of such systems are compatible with existing non- or minimally invasive surgical access devices or introducers, such as biopsy instruments, laparoscopic instruments, endovascular catheters, or equivalents. obtain. Alternatively, or in combination, embodiments of such a system may include its own introducer to provide access to the tumor site of interest. The systems described herein may be configured to access superficial tumors and / or less accessible and / or deeper inside the body. ..

It would also be desirable if improved methods, systems, and devices for drug candidate testing enabled simplified loading of drug candidates. The proposed embodiment of such a system may include, for example, one or more cartridges containing one or more drug candidates therein. Each cartridge may be configured for insertion into a delivery system that is preloaded with drug candidates and delivers the drug candidates from the cartridge to the tumor site of interest.

At least some of these objectives are met by the exemplary embodiments described below. Not all such aspects or benefits are achieved by any particular embodiment. Thus, the various embodiments achieve or achieve one benefit or group of benefits taught herein, without necessarily achieving other aspects or benefits that may be taught or suggested herein as well. It can be done in an optimizing fashion.

The present disclosure relates generally to medical devices, systems, and methods, more specifically to inject one or more fluids, such as one or more drug candidates or combinations, into tissues. Regarding the methods and devices used.

One aspect of the disclosure provides a fluid infusion system. In some embodiments, the fluid infusion system comprises an extension member having a proximal end and a distal end. In some embodiments, the extension member comprises an inner wall defining a lumen therein. In some embodiments, the fluid infusion system comprises a plurality of fluid delivery members. In some cases, the plurality of fluid delivery members are placed within the lumen of the extension member. In some cases, the plurality of fluid delivery members has a retracted configuration and an extended configuration. In some embodiments, the plurality of fluid delivery members are configured to extend outward from the distal end of the extension member in an extension configuration. In some embodiments, the plurality of fluid delivery members each comprises a distal end, a proximal end, an outlet port at the distal end, and an inner wall defining a fluid delivery lumen therein. In some embodiments, the fluid delivery lumen is fluidly coupled to the outlet port. In some embodiments, each fluid delivery lumen is fluidly independent of all other fluid delivery lumens of the plurality of fluid delivery members. In some embodiments, the fluid infusion system comprises multiple fluid delivery channels. In some embodiments, the plurality of fluid delivery channels are each fluidly coupled to one or more fluid delivery lumens of the plurality of fluid delivery members. In some embodiments, the fluid delivery mechanism is operably coupled to a plurality of fluid delivery channels, and the operation of the fluid delivery mechanism is such that the fluid is operably coupled from the plurality of fluid delivery channels to the plurality of fluid delivery members and from the outlet port. Let it pass outside.

In some embodiments, the operation of the fluid delivery mechanism is operably coupled to a plurality of fluid delivery members such that the delivery of the fluid occurs at the same time as the retreat of the fluid delivery member from the extending configuration to the retracting configuration. .. In some embodiments, the fluid delivery mechanism comprises a fluid delivery rod. In some embodiments, the plurality of fluid delivery members are configured to retreat from a protracted configuration to a retracted configuration at the same time as fluid delivery from the fluid delivery member. In some embodiments, the plurality of fluid delivery members are configured to be completely encapsulated within the lumen of the extension member in a retracted configuration.

In some embodiments, the extension member comprises a sheath, hypotube shaft, or needle. In some embodiments, the extension member comprises a metal. In some embodiments, the stretch member comprises a flexible material. In some embodiments, the stretch member comprises a rigid material. In some embodiments, the extension member has a length in the range of about 4 cm to about 250 cm. In some embodiments, the extension member has a length in the range of about 4 cm to about 20 cm. In some embodiments, the extension member has a length in the range of about 4 cm to about 20 cm. In some embodiments, the extension member has a length in the range of about 100 cm to about 250 cm. In some embodiments, the extension member has an outer diameter in the range of about 0.9 mm to about 3.5 mm. In some embodiments, the extension member has an outer diameter in the range of about 2 mm to about 4 mm. In some embodiments, the extension member has an outer diameter in the range of about 3 French to about 10 French. In some embodiments, the extension member has an outer diameter that is sized to fit within the working channel of a conventional biopsy access needle, conventional endoscope, or conventional vascular access sheath. In some embodiments, the extension member comprises a needle with a gauge number in the range of about 10 to about 20.

In some embodiments, the plurality of fluid delivery members comprises at least two fluid delivery members. In some embodiments, the plurality of fluid delivery members comprises 2 to 20 fluid delivery members. In some embodiments, the plurality of fluid delivery members comprises a plurality of needles or tubes. In some embodiments, the plurality of fluid delivery members comprises a plurality of pencil tip needles, blunt tip needles, or tilted tip needles. In some embodiments, the plurality of fluid delivery members comprises metal or plastic. In some embodiments, the plurality of fluid delivery members comprises a shape memory alloy. In some embodiments, the plurality of fluid delivery members comprises a flexible material. In some embodiments, the plurality of fluid delivery members comprises a rigid material. In some embodiments, the plurality of fluid delivery members each have an outer diameter in the range of about 0.05 mm to about 0.50 mm. In some embodiments, the plurality of fluid delivery members each have an outer diameter of about 0.25 mm. In some embodiments, the plurality of fluid delivery members are needles, each with a gauge number of about 28 to about 33. In some embodiments, the plurality of fluid delivery members are needles, each with a gauge number of about 31. In some embodiments, the fluid delivery lumens of the plurality of fluid delivery members each have a volume in the range of about 0.1 μl to about 10 μl. In some embodiments, each of the fluid delivery members has a length extending from the distal end of the extension member to the proximal end of the extension member. In some embodiments, the plurality of fluid delivery members each have a length in the range of about 4 cm to about 250 cm. In some embodiments, the plurality of fluid delivery members each have a length extending outward from the distal end of the extension member in an extension configuration in the range of about 5 mm to about 40 mm. In some embodiments, each of the fluid delivery members comprises at least one additional outlet port that is fluidly coupled to the fluid delivery lumen. In some embodiments, in the extending configuration, the plurality of fluid delivery members are each angled away from the vertical axis of the extension member. In some embodiments, the plurality of fluid delivery members are each angled away from the vertical axis of the extension member at an angle in the range of about 10 ° to about 90 °.

In some embodiments, the distal end of the extension member comprises an angular element that guides a plurality of fluid delivery members and is positioned to be angled away from the longitudinal axis of the extension member in an extending configuration. In some embodiments, in an extended configuration, the plurality of fluid delivery members each have a distance between the distal ends of the plurality of fluid delivery members in the range of about 1 mm to about 10 mm. Angle it away from the vertical axis of the extension member.

In some embodiments, the system further comprises a handle adjacent to the proximal end of the extension member.

In some embodiments, the system further comprises an actuator that is adjacent to the proximal end of the extension member and is operably coupled to multiple fluid delivery members, the actuation of the actuator from a retracted configuration to an extended configuration. , Or shift multiple fluid delivery members from an extended configuration to a retracted configuration. In some embodiments, the actuator is configured to retract a plurality of fluid delivery members from an extended configuration to a retracted configuration at a speed in the range of about 0.1 mm / sec to about 10 mm / sec. In some embodiments, the actuator comprises a mechanical actuator or an electromechanical actuator. In some embodiments, the actuator is manually operated. In some embodiments, the actuator is operated automatically.

In some embodiments, the fluid delivery mechanism is actuated by an actuator. In some embodiments, the fluid delivery mechanism comprises a mechanical actuator or an electromechanical actuator. In some embodiments, the fluid delivery mechanism comprises one or more of a plunger or pump. In some embodiments, the fluid delivery mechanism is operated manually. In some embodiments, the fluid delivery mechanism operates automatically. In some embodiments, the fluid delivery mechanism is configured to deliver fluid out of the outlet port at a flow rate in the range of about 0.1 μl / sec to about 10 μl / sec.

In some embodiments, the system is configured for fluid delivery from about 1 cm to about 300 cm below the skin surface. In some embodiments, the system is configured for fluid delivery from about 1 cm to about 30 cm below the skin surface. In some embodiments, the system is configured for fluid delivery from about 4 cm to about 20 cm below the skin surface. In some embodiments, the system is configured for fluid delivery from about 100 cm to about 250 cm below the skin surface.

In some embodiments, the plurality of fluid delivery channels comprises a fluid delivery lumen of a plurality of fluid delivery members. In some embodiments, the fluid delivery lumen of the plurality of fluid delivery members is a plurality of fluid delivery channels. In some embodiments, the fluid delivery mechanism comprises a plurality of fluid delivery mechanisms, each of which is operably coupled to a single fluid delivery channel of the plurality of fluid delivery channels.

In some embodiments, the system further comprises an imaging system for perioperative imaging of the fluid infusion system in use.

In some embodiments, the system is further fluidly coupled to one or more of the fluid delivery lumens, or one or more of the fluid delivery channels. Includes one or more cartridges. In some embodiments, the plurality of fluid delivery channels each have a volume in the range of about 10 μl to about 500 μl.

In some embodiments, the system further comprises a population of fluorescence tracking microspheres (FTMs). In some embodiments, the fluorescence tracking microspheres have a diameter of 5 micrometers to 10 micrometers. In some embodiments, the fluorescence tracking microsphere comprises polystyrene. In some embodiments, the system further comprises a plurality of populations of fluorescence tracking microspheres (FTMs).

In some embodiments, the system further comprises a volume selector.
In some embodiments, the system further comprises a plurality of cartridges.

One aspect of the disclosure is a method of injecting fluid into a tumor within the patient's body, a step of providing a fluid infusion system, in which the fluid infusion system is proximal and distal. The extension member, the plurality of fluid delivery members arranged in the lumen of the extension member, and the plurality of fluid delivery channels, each of the plurality of fluid delivery channels is each of the plurality of fluid delivery members. A step of fluidly coupling into a single fluid delivery lumen, a step of inserting the distal end of an extension member into the body with multiple fluid delivery members retracted, and multiple fluid deliveries. A plurality of steps, one step of positioning the distal end of the extension member in close proximity to the tumor with the member retracted, and the other step of extending multiple fluid delivery members into the tumor from the distal end of the extension member. A step of injecting a plurality of fluids into a tumor from a fluid delivery member, each of which is fluidly independent of all other of the plurality of fluid delivery members. Provide methods, including and.

In some embodiments, the method further comprises retracting the plurality of fluid delivery members from the tumor into the distal end of the extension member. In some embodiments, the step of retracting the plurality of fluid delivery members occurs in parallel with the step of injecting the plurality of fluids. In some embodiments, the step of retracting the plurality of fluid delivery members is a step of retracting the plurality of fluid delivery members such that the plurality of fluid delivery members are completely encapsulated within the lumen of the extension member. include. In some embodiments, the step of retracting the plurality of fluid delivery members comprises retracting the plurality of fluid delivery members at a speed in the range of about 0.1 mm / sec to about 10 mm / sec.

In some embodiments, the method further comprises removing the distal end of the extension member from the body with the plurality of fluid delivery members retracted. In some embodiments, the method further comprises excising at least a portion of the tumor for analysis. In some embodiments, the method further comprises loading a plurality of fluids into a plurality of fluid delivery channels prior to inserting the distal end of the extension member into the body. In some embodiments, the method further comprises imaging the fluid infusion system before and after surgery.

In some embodiments, the extension member comprises a sheath, hypotube shaft, or needle. In some embodiments, the extension member comprises a metal. In some embodiments, the stretch member comprises a flexible material. In some embodiments, the stretch member comprises a rigid material. In some embodiments, the extension member has an outer diameter in the range of about 0.9 mm to about 3.5 mm. In some embodiments, the extension member comprises a needle with a gauge number in the range of about 10 to about 20.

In some embodiments, the step of inserting the distal end of the extension member into the body is a conventional biopsy access needle, a conventional endoscopy, in which the distal end of the extension member is pre-positioned within the body. Includes the step of inserting into a mirror, or the working channel of a conventional vascular access sheath.

In some embodiments, the plurality of fluid delivery members comprises at least two fluid delivery members. In some embodiments, the plurality of fluid delivery members comprises 2 to 20 fluid delivery members. In some embodiments, the plurality of fluid delivery members comprises a plurality of needles or tubes. In some embodiments, the plurality of fluid delivery members comprises metal or plastic. In some embodiments, the plurality of fluid delivery members comprises a shape memory alloy. In some embodiments, the plurality of fluid delivery members comprises a flexible material. In some embodiments, the plurality of fluid delivery members comprises a rigid material. In some embodiments, the plurality of fluid delivery members each have an outer diameter of about 0.05 mm to about 0.50 mm. In some embodiments, the plurality of fluid delivery members are needles, each with a gauge number of about 28 to about 33.

In some embodiments, the step of injecting the plurality of fluids comprises injecting the plurality of fluids at a flow rate in the range of about 0.1 μl / sec to about 10 μl / sec. In some embodiments, the step of injecting the plurality of fluids comprises injecting a volume of each of the plurality of fluids in the range of about 10 μl to about 500 μl from each of the plurality of fluid delivery members.

In some embodiments, each of the fluid delivery members has a length extending from the distal end of the extension member to the proximal end of the extension member. In some embodiments, the plurality of fluid delivery members each have a length in the range of about 4 cm to about 250 cm.

In some embodiments, the step of extending the plurality of fluid delivery members extends the length of each of the plurality of fluid delivery members in the range of about 5 mm to about 40 mm from the distal end of the extension member to the tumor. Includes steps to extend within. In some embodiments, the step of extending the plurality of fluid delivery members is multiple from the distal end of the extension member such that the plurality of fluid delivery members are angled away from the longitudinal axis of the extension member. Includes the step of extending the fluid delivery member.

In some embodiments, the distal end of the extension member comprises an angular element that guides a plurality of fluid delivery members and is positioned to be angled away from the longitudinal axis of the extension member in an extending configuration.

In some embodiments, the step of injecting the plurality of fluids comprises producing a plurality of distinctly different fluid columns within the tumor.

In some embodiments, the fluid infusion system used in the method further comprises a handle, wherein the fluid delivery mechanism is operably coupled to a plurality of fluid delivery channels. The step of injecting the fluid includes the step of activating the fluid delivery mechanism. In some embodiments, the fluid delivery mechanism comprises the step of manually operating the fluid delivery mechanism. In some embodiments, the step of activating the fluid delivery mechanism comprises the step of automatically activating the fluid delivery mechanism. In some embodiments, the fluid delivery mechanism comprises a mechanical actuator or an electromechanical actuator. In some embodiments, the fluid delivery mechanism comprises one or more of a plunger or pump. In some embodiments, the fluid infusion system further comprises an actuator that is adjacent to the proximal end of the extension member and is operably coupled to a plurality of fluid delivery members. In some embodiments, the step of extending the plurality of fluid delivery members comprises activating the actuator.

In some embodiments, the step of activating the actuator includes the step of manually activating the actuator. In some embodiments, the step of injecting the plurality of fluids comprises the step of activating the actuator. In some embodiments, the step of activating the actuator comprises the step of automatically activating the actuator. In some embodiments, the actuator comprises a mechanical actuator or an electromechanical actuator. In some embodiments, the actuator comprises one or more of a thumbwheel or an electric actuator. In some embodiments, the step of injecting the plurality of fluids comprises injecting the plurality of fluids from about 0.2 cm to about 20 cm below the skin surface. In some embodiments, the step of injecting the plurality of fluids comprises injecting the plurality of fluids from about 1 cm to about 30 cm below the skin surface. In some embodiments, the step of injecting the plurality of fluids comprises injecting the plurality of fluids from about 4 cm to about 20 cm below the skin surface. In some embodiments, the step of injecting the plurality of fluids comprises injecting the plurality of fluids from about 100 cm to about 250 cm below the skin surface. In some embodiments, the fluid comprises one or more therapeutic agents. In some embodiments, the step of injecting the plurality of fluids comprises injecting different fluids into the tumor from each of the plurality of fluid delivery members. In some embodiments, the step of injecting the plurality of fluids comprises injecting the same fluid into the tumor from each of the plurality of fluid delivery members. In some embodiments, the tumor is the patient's skin, breast, brain, prostate, colon, rectum, kidney, pancreas, lung, liver, heart, stomach, intestine, ovary, testis, cervix, lymph nodes, thyroid. Located in the esophagus, head or neck, eyes, bones, or bladder. In some embodiments, the fluid comprises a population of fluorescence tracking microspheres (FTMs). In some embodiments, the plurality of fluids comprises a plurality of populations of fluorescence tracking microspheres.
(Built-in by reference)

All publications, patents, and patent applications described herein are the same as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent, it is incorporated herein by reference.

The novel features of the present invention are described in detail in the appended claims. A further understanding of the features and advantages of the present invention will be obtained by reference to the embodiments and accompanying drawings for carrying out the following inventions that describe exemplary embodiments in which the principles of the present disclosure are utilized.

FIG. 1 shows a schematic view of a thin fluid injection system according to an embodiment.

FIG. 2 shows a schematic representation of a thin fluid injection system with an extended delivery member according to an embodiment.

FIG. 3 shows a schematic view of a thin fluid injection system according to an embodiment.

FIG. 4A shows a schematic view of a portion of a thin fluid injection system and cartridge according to an embodiment.

FIG. 4B shows a schematic diagram illustrating loading of a thin fluid injection system with a cartridge according to an embodiment.

FIG. 5A shows a schematic view of a thin fluid injection system according to an embodiment.

FIG. 5B shows a schematic representation of a thin fluid infusion system with an extended delivery member according to an embodiment.

FIG. 5C shows a schematic view of a portion of the thin fluid injection system shown in FIG. 5B according to an embodiment.

FIG. 6A shows a schematic view of a thin fluid injection system according to an embodiment.

FIG. 6B shows a portion of the thin fluid injection system shown in FIG. 6A according to an embodiment.

FIG. 7 shows an image of the internal mechanism of the thin fluid injection system according to the embodiment.

FIG. 8 shows a schematic view of a thin fluid injection system according to an embodiment.

FIG. 9 shows a cross-sectional view of an extension member of a thin fluid injection system according to an embodiment.

FIG. 10A shows a schematic representation of a thin fluid injection system with an unextended configuration and a fluid delivery member according to an embodiment.

FIG. 10B shows the system of FIG. 10A with a fluid delivery member in an extended configuration, according to an embodiment.

FIG. 11A shows an exemplary extension member with a fluid delivery member in an unextended configuration, according to an embodiment.

FIG. 11B shows an exemplary extension member with a fluid delivery member in an extended configuration, according to an embodiment.

FIG. 12A shows the distal end of an exemplary extension member with a fluid delivery member in an unextended configuration, according to an embodiment.

FIG. 12B shows the distal end of an exemplary extension member with a fluid delivery member in an extended configuration, according to an embodiment.

FIG. 13A shows a schematic representation of the target tissue following infusion by a thin fluid infusion system, depicted in a cross-sectional view perpendicular to the vertical axis of the system, according to an embodiment.

FIG. 13B shows a perspective view of the injection column in the target tissue following injection by the thin fluid injection system according to the embodiment.

FIG. 13C shows a perspective view of the injection column in the target tissue following injection by the thin fluid injection system according to the embodiment.

FIG. 14 shows a schematic representation of a thin fluid infusion system with a fluid delivery member extending inside a target tissue according to an embodiment.

FIG. 15A shows an exemplary thin fluid infusion system with a fluid delivery member in an unextended configuration inside a simulated target tissue according to an embodiment.

FIG. 15B shows an exemplary system of FIG. 15A with a fluid delivery member extending within a simulated target tissue according to an embodiment.

FIG. 15C shows the system of FIG. 15A during simultaneous infusion of fluid into a simulated target tissue and simultaneous retreat of a fluid delivery member according to an embodiment.

FIG. 16A shows a schematic representation of a thin fluid injection system according to an embodiment prior to fluid injection with a fluid delivery member in an unextended configuration.

FIG. 16B shows a schematic representation of a thin fluid injection system according to an embodiment prior to fluid injection with a fluid delivery member in an extended configuration.

FIG. 16C shows a schematic view of a post-fluid injection thin fluid injection system with an unextended configuration and a fluid delivery member according to an embodiment.

FIG. 16D shows a schematic representation of a thin fluid injection system according to an embodiment prior to fluid injection with a fluid delivery member in an extended configuration.

FIG. 16E shows the system of FIG. 16D after simultaneous fluid injection and retraction of the fluid delivery member according to the embodiment.

FIG. 17 shows exemplary steps of a method of injecting fluid into a tumor in a subject's body using a fluid infusion system according to an embodiment.

FIG. 18A shows an image of a thin fluid injection system with a volume selector, according to an embodiment.

FIG. 18B shows an image of the volume selector according to the embodiment.

FIG. 19A shows a schematic view of a thin fluid injection system with a tip cap according to an embodiment.

FIG. 19B shows a schematic view of the tip cap according to the embodiment.

FIG. 20A shows a cartridge according to an embodiment.

FIG. 20B shows a cartridge according to an embodiment.

21A-21D show embodiments, methods for delivering and detecting one or more agents within a target tissue.

(Detailed explanation)
In the embodiments for carrying out the following inventions, the accompanying drawings forming a part of the present specification are referred to. In the figure, similar symbols typically identify similar components unless the context determines otherwise. The embodiments, figures, and exemplary embodiments for carrying out the invention are not intended to be limited. Other embodiments may be utilized and other modifications may be made without departing from the scope of the subject matter presented herein. In general, the aspects of the disclosure as described herein and illustrated in the drawings are all arranged and substituted in a wide variety of different configurations, all of which are expressly discussed herein. It will be easily understood that they can be combined, separated, and designed.

Although certain embodiments and examples are disclosed below, the subject matter of the invention extends beyond the specifically disclosed embodiments to other alternative embodiments and / or uses, as well as modifications and equivalents thereof. do. Accordingly, the scope of the claims attached herein is not limited by any of the particular embodiments described below. For example, in any method or process disclosed herein, the actions or actions of the method or process may be performed in any suitable order and are not necessarily limited to any particular disclosed order. .. The various actions can, in turn, be described as multiple discrete actions in a manner that can help to understand certain embodiments, however, the order of description implies that these actions are order-dependent. Should not be interpreted. In addition, the structures, systems, and / or devices described herein can be described as integrated components or as separate components.

Certain aspects and advantages of these embodiments are described for the purpose of comparing the various embodiments. Not all such aspects or benefits are achieved by any particular embodiment. Thus, for example, one advantage or advantage as taught herein, without necessarily achieving other aspects or advantages as various embodiments may be taught or suggested herein as well. It can be performed in a manner that achieves or optimizes the herd.

The present disclosure describes thin fluid infusion devices and systems, and how to use them. The thin fluid infusion devices and systems disclosed herein can provide advantages over existing devices, systems, and methods, for example in diagnostic and / or therapeutic applications. In some cases, the thin fluid infusion system disclosed herein (eg, System 100) is used for drug delivery to in-situ cancer. Those skilled in the art will appreciate that the devices, systems, and methods disclosed herein can be used in multiple anatomical areas and in multiple surgical procedures. Also, the insertion of fluid infusion systems disclosed herein and / or the delivery of one or more agents as disclosed herein is a medical treatment that is not a physician (eg, a physician) or a physician. It will be appreciated by those skilled in the art that it can be performed by a person skilled in subcutaneous injection, such as a specialist (eg, a venous practitioner, a clinical technician, a nurse, a field nurse, or a physician's assistant). The device may be used, for example, for preclinical, in vitro, or in vitro drug testing. The method may be performed on human tissue or tissue sample, or on animal tissue or tissue sample.

FIG. 1 shows a thin fluid injection system 100 including an actuator 250 and an extension member 110. As will be appreciated by those skilled in the art, the dimensions and structure of thin fluid infusion systems disclosed herein include one or more fluids to the target tissue (eg, therapeutic and / or diagnostic agents). Allows minimally invasive delivery (which may include). As disclosed herein, one or more fluids are loaded into chamber 400 (eg, in one or more cartridges 432) and housed in extension member 110. It may be delivered to the target tissue (eg, tumor tissue or part thereof) via one or more fluid delivery members 320. The extension member 110 can be connected to the housing of the fluid injection system 100 at the proximal end 113 of the extension member 110. In some cases, the proximal end 113 of the extension member 110 may include a distal joint 190. The distal coupling 190 can be a mounting interface (eg, a clip or luer lock connector). In some cases, the coaxial sheath can be slid across the extension member 110 and coupled to the distal coupling 190.

The actuator 250 is among the various means for driving the syringe body 260 and the fluid delivery member 320 within the housing of the fluid injection system 100 (which may include a contoured outer wall with a handgrip 170 (or handle)). Can be one of. In many cases, the actuator 250 comprises a lever arm connected to an actuator column 254 that drives the syringe body 260 inside the housing of the fluid injection system 100 via a syringe rod 257. In various embodiments, the actuator 250 can be manually operated (eg, by compressing the actuator 250 against the housing of the fluid injection system 100). In some cases, the actuator 250 may include a mechanized actuator in which some or all of the force used in the operation of the syringe body 260 can be provided by the electromechanical mechanism. Actuator 250 can extend one or more fluid delivery members from the distal end 114 of the extension member 110 (eg, into tissue of interest, such as target tumor tissue).

FIG. 2 shows a thin fluid injection system 100 with a lever arm of an engaged (eg, pressed) actuator 250. Engaging (eg, pressing) the actuator 250 allows one or more fluid delivery members to extend out of the extension member 110 via the distal end 114 of the extension member 110. .. The fluid delivery member 320 can be deflected (eg, unfolded) away from the vertical axis of the fluid injection system 100. A representative example of a plurality of fluid delivery members 320 extending as they extend from the distal end 114 of the extension member 110 is shown in FIG. In some cases, the distal end 114 of the extension member is one when the actuator 250 is engaged (eg, when the syringe body 260 is operated distally within the housing of the fluid infusion system 100). Alternatively, the fluid delivery member 320 may be provided with one or more angular elements 115 (eg, a magnifying mechanism) capable of deflecting the fluid delivery member 320 further away from the longitudinal axis of the fluid injection system 100. The angle element 115 may include one or more guides, which may include angled channels through which the fluid delivery member 320 may pass. Representative examples of the angular element 115 are shown in FIGS. 12A and 12B. In some embodiments, one or more fluid delivery members 320 may extend in line with the vertical axis of the fluid injection system 100 when the actuator 250 is engaged. When the actuator 250 is engaged, the fluid delivery member 320 extends in line with the vertical axis of the fluid injection system 100, in some cases the distal end 114 of the extension member 110 is not angled. It comprises a guide element (eg, through which the fluid delivery member 320 may pass).

In some cases, the distal end 114 is shaped to penetrate (eg, puncture) tissue. For example, the distal end 114 can have, for example, a pointed or sharp end to penetrate the skin or fibrous tissue. In many cases, the distal end 114 can have a bullet-shaped or rounded end. Such a bullet-shaped or rounded end of the distal end 114 may be sufficient to penetrate the skin or fibrous tissue, however, the bullet-shaped or rounded distal end 114 is internal. It can be advantageous for advancing the stretch member through the tissue or tissue inside the subject, as it can avoid damaging (eg, puncturing) other tissues such as organs. In some cases, a guide element, such as the angle element 115, can be formed to assist the penetration of the extension member 110 into or through the tissue.

In some cases, the lever arm of the actuator 250 is aligned (eg, in contact) with the lever arm recess 172 of the housing of the fluid injection system 100 (eg, by fully engaging the actuator 250). ) May be installed. The lever arm recess 172 can allow the actuator 250 to be pushed to a position more coplanar with the surface of the housing of the fluid injection system 100, which is used by the user of the fluid injection system 100. In the meantime, it can help maintain stable control over the fluid injection system 100. A typical embodiment of the lever arm recess 172 is shown in FIG.

FIG. 3 shows a cross-sectional image of the thin fluid injection system 100. The actuator 250 of the thin fluid injection system 100 may include an actuator coupling portion 252. The actuator coupling portion 252 can be coupled to the actuator strut 254 (eg, rotatably coupled, eg, the actuator coupling portion 252 is a hinge joint). The actuator strut 254 can be coupled to the strut joint 256 (eg, rotatably coupled, eg, the strut coupling 256 is a hinge joint). The strut coupling portion 256 can be coupled to the syringe rod 257 and / or the syringe body 260. In some cases, the strut joints are fixed and attached to the lind rod 257 and / or the syringe body 260, eg, the strut joint 256 and the syringe rod 257, the syringe body 260, or the syringe rod 257 and the syringe body 260. Rotation or translation between both is not possible.

Engaging the actuator 250 (eg, pressing the lever arm of the actuator 250) causes the strut 254 (eg, via the syringe rod 257 in some cases) to exert a force on the syringe body 260. This allows the syringe body 260 to slide and parallel, eg, distally along the vertical axis of the fluid injection system 100, through the interior of the fluid injection system 100 (eg, through the syringe body shaft 268). (See, for example, FIGS. 5A, 5B, and 5C). In some cases, disengaging the actuator 250 (eg, releasing the lever arm of the actuator 250) allows the syringe body to translate proximally along the longitudinal axis of the fluid injection system 100. (See, for example, FIGS. 6A and 6B). In some cases, engaging the actuator 250 causes the syringe rod 257 to move distally along the vertical axis of the fluid injection system 100, eg, inside the fluid injection system 100 (eg, syringe rod shaft 520). It can be slidably moved in parallel through. In some cases, disengaging the actuator 250 (eg, releasing the lever arm of the actuator 250) causes the syringe rod 257 to translate, for example, in the proximal direction along the longitudinal axis of the fluid injection system 100. It can be made possible to translate completely or partially through the interior of the injection system 100. The lever arm of the actuator 250 can be coupled (eg, rotatably coupled) to the housing of the fluid injection system 100 by the actuator hinge 251. In some cases, the actuation of the actuator 250 causes the lever arm of the actuator 250 to rotate around the actuator hinge 251.

In some cases, the housing of the fluid injection system 100 may include strut channels 255 to allow the actuator strut 254 to move along the longitudinal axis (eg, during actuation of the actuator 250). can. The housing of the fluid injection system 100 may include an actuator coupling cutout 253. In some cases, the actuator coupling cutout 253 is molded and positioned within the housing of the fluid injection system 100 to receive the actuator coupling portion 242 (eg, the lever arm of the actuator 250 is pressed). In some cases, the actuator coupling cutout 253 can allow the actuator coupling portion 252 to move inside the maximum radius of the housing of the fluid injection system 100 (eg, this is the actuator 250 It can be made possible to be pressed to a point that is coplanar or in contact with the outer surface of the housing of the injection system 100).

One or more fluid delivery members can be attached to the syringe body 260. Translation of the syringe body 260 through the syringe body shaft 268 allows one or more fluid delivery members 320 to be translated distally through the extension member 110. In some cases, the actuator 250 engages the distance that the fluid delivery member 320 of the syringe body 260 and / or one or more thereof translates distally or proximally along the longitudinal axis of the fluid infusion. For example, it may depend on the degree to which it is pressed) or disengaged (eg, released). In some cases, engaging the actuator 250 causes one or more fluid delivery members 320 to extend distally from the distal end 114 of the extension member 110.

The syringe body spring 264 can be used to resist the distal translation of the syringe body 260 along the vertical axis of the fluid infusion system 100. In some cases, the syringe body spring 264 is located between the distal end 269 of the syringe body shaft 268 and the shoulder portion 266 of the syringe body 260. Actuating the actuator 250 (eg, engaging the actuator 250 by pressing the lever arm of the actuator 250) (eg, bringing the syringe body shoulder 266 closer to the distal end 269 of the syringe body shaft 268). By translating the syringe body 260 so that it can cause compression of the syringe body spring 264). Decoupling the actuator 250 (eg, releasing the lever arm of the actuator 250) can allow the syringe body spring to extend and place the syringe body 260 on the vertical axis of the fluid injection system 100. It can be translated proximally along. The syringe rod 257 may translate with the syringe body 260 when the actuator 250 is not engaged. Proximal translation of the syringe rod 257 and / or proximal translation of the syringe body 260, for example, when the actuator 250 is not engaged (eg, as shown in FIG. 3) (eg, strut coupling). A force can be applied to the actuator 250 by the actuator column 254 (via the portion 256 and the actuator coupling portion 252) to cause the actuator 250 to be in an unengaged (eg, unpressed) configuration.

The syringe body spring 264 can be held in a compressed state when the actuator 250 is not engaged (eg, when the actuator 250 is in an unengaged configuration). For example, the syringe body spring 264 can be held in a compressed state between the distal end of the syringe body shaft 268 and the syringe body 260. In some cases, the syringe body 260 is urged against the syringe shaft shoulder 267 by the syringe body spring 264. In some cases, the syringe body shaft 268 and the syringe rod shaft 520 are connected internal spaces of the fluid injection system 100. In some cases, the syringe shaft shoulder 267 represents the distal end of the syringe rod shaft 520 and the proximal end of the syringe body shaft 260. The length and / or spring constant of the syringe body spring 264 may be designed or selected such that the desired force is required to actuate the actuator 250. For example, the syringe body spring 264 may otherwise reduce the user's control over the position and / or orientation of the device during use, or excessive force may lead to imperfect operation of the actuator 250. May be chosen to have a length and / or spring constant so that it is not required to operate. In certain embodiments, the actuator 250 receives or is inadvertently struck by its own weight, which can lead to an unintended extension of the fluid delivery member 320 and / or squeezing of fluid from the fluid delivery member 320. In some cases, it is useful to select the syringe body spring 264 to have a length and / or spring constant so that it does not work.

The thin fluid injection system 100 can include one or more fluid delivery members 320. The fluid delivery member 320 can comprise a channel through which the fluid can flow. In many cases, the fluid injection system 100 includes a plurality of fluid delivery members 320. For example, the fluid injection system 100 includes 2, 3, 4, 5, 6, 7, 8, 9, 10 pieces, 10 to 20, 20 to 30, 30 to 40 pieces, 40 to 50 pieces, or 50 pieces. A fluid delivery member 320 that exceeds the number can be provided. More target tissue sites may be infused with fluid by increasing the number of fluid delivery members 320 comprising the fluid infusion system 100. The fluid injection system 100 can inject fluid into the target tissue in a well-controlled pattern (eg, a pattern that may include one or more columnar fluid injections). In some cases, the fluid infusion system 100, comprising a plurality of fluid delivery members 320 (eg, so that the effects of each infusion can be compared, for example, in vitro, in vitro, in vivo, or in vitro). It will allow multiple different fluids to be injected into one or more parts of the target tissue.

The fluid delivery member 320 provides a fluid path (eg, to an injection site within the target tissue adjacent to or near the distal end of the fluid delivery member 320) from the fluid source (eg, cartridge 432) to the target tissue. For example, a part of a continuous fluid path or a valved fluid path) can be provided. In some cases, the proximal end 327 of the fluid delivery member 320 is at a greater radial distance from the longitudinal axis of the fluid injection system 100 than the distal end 328 of the fluid delivery member 320. The fluid delivery member 320 is advantageous in minimizing the diameter of the extension member (eg, reducing the size of the access path used to advance the extension member 110 into or through the tissue). It can be provided with one or more bends that can be. In some cases, the number and / or angle of bends within the fluid delivery member 320 depends on the radius from which the proximal end of the fluid delivery member 320 derives from the longitudinal axis of the fluid injection system 100. In some cases, the radius from which the proximal end of the fluid delivery member 320 derives from the vertical axis of the fluid injection system 100 is that of the syringe body 260, syringe body spring 264, syringe body shaft 268, syringe rod shaft 520, or cartridge 432. It depends on the thickness and / or diameter of one or more of them. In certain embodiments, the thickness and / or diameter of one or more of the syringe body 260, syringe body spring 264, syringe body shaft 268, syringe rod shaft 520, or cartridge 432 is the fluid injection system 100. It can be minimized to reduce the overall diameter or to reduce the number or angle of bends within the fluid delivery member 320. In some cases, the radius from which the proximal end of the fluid delivery member 320 derives from the vertical axis of the fluid injection system 100 is in the path of the fluid delivery channel 270 (eg, the path of the fluid delivery channel 270 through the syringe body 260). Dependent.

In some cases, one or more fluid delivery members 320 are coupled to the syringe body 260, for example, at the proximal end 327 of the fluid delivery member 320. In some cases, one or more fluid delivery members 320 communicate with one or more fluid delivery channels 270. For example, the proximal end 327 of the fluid delivery member 320 can communicate with the fluid delivery channel 270, for example, in the delivery channel interface 290.

The fluid delivery channel 270 can be a fluid path connecting the fluid source (eg, cartridge 432) and the fluid delivery member 320. The fluid delivery channel 270 may include a syringe body 260, a cartridge abutment 410, or a portion of one or more of the cartridge interfaces 420. The thin fluid injection system 100 can include a plurality of fluid delivery channels 270. For example, a thin fluid injection system can include as many fluid delivery channels 270 as the fluid delivery member 320 and / or the cartridge chamber 400. In some cases, the thin fluid infusion system can include multiple fluidly independent pathways that connect the fluid source (eg, cartridge 432) to the target tissue. For example, a fluid-independent path can include a fluid source, a fluid delivery channel 270, and a fluid delivery member 320, and a fluid-independent path (eg, fluid communication with another fluid source). It does not communicate with another fluid source (via the fluid delivery channel 270 and / or the fluid delivery member 320). In some embodiments, the fluid injection system 100 is independent of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 10-20, 20-50, or more than 50. It has a fluid path. In some cases, inclusion of multiple fluidly independent pathways within the fluid infusion system 100 allows for independent treatment and / or subsequent independent analysis of multiple diagnostics and / or multiple therapeutic agents. ..

In some cases, the fluid delivery channel 270 or a portion thereof can serve as a fluid reservoir. For example, at least a portion of the fluid delivery channel 270 can include fluid to be delivered to the target tissue or a portion thereof using the fluid injection system 100. In some cases, the fluid delivery channel 270 is primed with fluid before the fluid infusion system 100 is used to inject the fluid into the target tissue or a portion thereof. As further disclosed herein, the fluid 480 in a fluid source (eg, cartridge 432) can be pressured while communicating with the fluid delivery channel 270, which is the fluid 480. Can flow from the fluid source into the fluid delivery channel 270.

4A and 4B show typical embodiments of loading the cartridge 432 into the fluid injection system 100. One or more fluids contained within the cartridge 432 can communicate with the fluid delivery channel 270 by engaging the cartridge plunger 440 with the cartridge interface 420. In some cases, fluid from one or more of the cartridges 432 (eg, as a result of the cartridge 432 being urged by the cartridge abutment 410 against the hole edge of the cartridge retainer 430) It can be pressurized when loaded into the cartridge retention device 430. In some cases, pressurization of the fluid in the cartridge 432 during loading of the cartridge 432 into the fluid injection system 100 can fill or partially fill the fluid delivery channel 270.

Often, a fluid delivery mechanism 280 (eg, a fluid delivery rod 280) is used to drive fluid from at least a portion of the fluid delivery channel 270 toward the distal end 114 of the fluid delivery member 320. The fluid delivery mechanism 280 may include one or more fluid delivery rods. The fluid delivery rod 280 can be slidably disposed within at least a portion of the fluid delivery channel 270. In some cases, the fluid delivery rod 280 has a parallel movement of the fluid delivery rod 280 that follows at least a portion of the fluid delivery channel 270 (eg, a distal parallel movement with respect to the fluid injection system 100). It is sized to increase the pressure inside at least part of the channel 270 and, for example, to cause squeezing of the fluid from the distal end of the fluid delivery member 320 after the actuator 250 has been activated. As shown in FIG. 3, the fluid delivery rod 280 can be introduced into the fluid delivery channel 270 at a bend in the fluid delivery channel 270. For example, the distal end 284 of the extension member can be positioned at or adjacent to the bend in the fluid delivery channel 270. Also, the fluid delivery channel 270 may include a three-way junction (eg, a T-joint), with the fluid delivery rod adjacent to the three-way junction and downstream (eg, distal) thereof. It is also considered to stand still in the arm at the three-way junction in line with part of the 270.

The fluid delivery channel 270 can communicate with the purge channel 271. The purge channel 271 can communicate with the air outside the fluid injection system 100. In some cases, the purge channel 271 passes through the components of system 100 (eg, syringe body 260) and / or between two or more components of system 100 (eg, syringe body 260 and system 100). A channel and / or a gap is provided between the housing and / or the housing. In some cases, air (or another gas) present in the channel, reservoir, or cartridge of the fluid infusion system 100 can be ventilated through the purge channel 271. The purge channel 271 can be useful, for example, during loading or infusion, as excess gas or pressure can be released through the purge channel 271.

The fluid injection system 100 can include a lockout assembly 500. The lockout assembly 500 can be coupled (eg, slidably coupled) to the syringe rod 257. In some cases, the syringe rod 257 is rigidly coupled to the syringe rod 257. In some cases, the syringe rod 257 can pass through a hole or channel within the lockout assembly 500 (eg, a hole or channel within the lockout assembly 500).

The lockout assembly 500 can include one or more lockout pins 501. The lockout assembly 500 can include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more lockout pins 501. One or more lockout pins 501 of the lockout assembly can be located on the circumferential side of the lockout assembly 500. For example, one or more lockout pins 501 can project from the circumferential side of the lockout assembly 500. The lockout assembly 500 can include one or more springs. In some cases, one or more lockout pins 501 of the lockout assembly 500 can be coupled to one or more springs of the lockout assembly 500. In some cases, a spring in one or more of the lockout assembly 500 is a lockout pin that is outward (eg, radial outward) from the lockout assembly 500 and one or more of the lockout assembly 500. It can be configured to urge 501. The lockout pin 501 can be configured to moor the lockout assembly 500 in a longitudinal location along the syringe rod shaft 520. In some cases, one or more lockout pins 501 of the lockout assembly 500 can be urged outward with respect to the inner surface of the syringe rod shaft 520. In some cases, one or more lockout pins 501 of the syringe rod shaft 520 (eg, as a result of being urged against the inner surface of the syringe rod shaft 520 by the spring of the lockout assembly 500). The lockout assembly can be anchored in the longitudinal location of the syringe rod shaft 520 extending into one or more lockout stops 560. In some cases, one or more lockout pins 501 are urged against the inner surface of the syringe rod shaft 520 before the actuator 250 is engaged, and when the actuator 250 is engaged, The lockout pin of one or more of 501 slides longitudinally along the inner surface of one or more of the syringe rod shaft 520. Where the syringe rod shaft 520 comprises one or more lockout stops 560 (eg, along the inner surface of the syringe rod shaft 520), one or more lockout pins 501 (eg, along the inner surface of the syringe rod shaft 520). At least a portion (as a result of engaging the actuator 250 and / or urging the lockout pin 501 against the syringe rod shaft 520) using one or more springs of the lockout assembly 500). It can be configured to extend into one or more lockout stops 560. In some cases, the lockout assembly 500 is longitudinally extended when one or more lockout pins 501 are at least partially extended within one or more lockout stops 560. It is prevented from translating (eg, distally, proximally, or both distally and proximally).

In some embodiments where the fluid injection system 100 is a multi-use system, one or more lockout pins 501 are one or more lockout stops on one side of the syringe rod shaft 520 (eg, one or more lockout stops). It is configured to be releasably engaged with the portion 560). In some cases, one or more lockout pins can be wedge-shaped. For example, the lockout pin can have an angled or sloping surface facing the distal end of the fluid injection system 100. In some cases, one or more members, such as rods or sticks, engage one or more lockout pins 501 from one or more lockout stops 560 (eg,). Can be introduced into the fluid injection system 100 (via one or more holes, ports, or channels in the proximal end of the fluid injection system 100). Members configured to engage one or more lockout pins 501 from one or more lockout stops 560 can have a pointed or wedge-shaped distal end. In some cases, for one or more engaged lockout pins 501 (eg, through one or more access holes, ports, or channels within the proximal end of system 100). Pushing one or more members back into the body of the lockout assembly 500 (eg, by compressing one or more springs of the lockout assembly 500). Or more lockout pins 501 can be pushed. Actuating one or more lockout pins 501 from one or more lockout stops 560 (eg, force is applied directly or indirectly to the lockout assembly 500 by the syringe rod spring 510). Allowing one or more components of the system 100, such as the lockout assembly 500, to travel proximally and longitudinally when the actuator 250 is released (as a result of being done). Can be done. FIG. 7 shows an image of the internal mechanism of a fluid injection system 100 comprising a lockout assembly 500, a lockout pin 501, and a syringe rod spring 510.

The fluid injection system 100 can include a syringe rod fixture 258 (eg, a syringe rod pin). The syringe rod fixture 258 may be coupled (eg, rigidly coupled) to the syringe rod 257. Often, the syringe rod fixture 258 is coupled to the syringe rod 257 at the longitudinal location of the syringe rod 257, which is proximal to the lockout assembly 500 (eg, relative to the vertical axis of the fluid injection system 100). .. On some sides, the syringe rod fixture 258 prevents the lockout assembly from sliding off the proximal end of the syringe rod 257 (eg, due to the force exerted by the syringe rod spring 510). .. On some aspects, the syringe rod fixture 258 does not prevent the syringe rod 257 from sliding through the lockout assembly 500 (eg, proximal to the longitudinal axis of the fluid injection system 100).

The fluid injection system 100 can include one or more lockout stops 560. The lockout stop portion 560 can be fixedly attached to the syringe rod shaft 520. In many cases, the lockout stop 560 is attached (eg, fixed) to the syringe rod shaft 520 at different locations along the vertical axis of the fluid injection system 100. In many cases, a plurality of lockout stops 560 are attached to the syringe rod shaft 520 at a plurality of locations around the inner circumference of the syringe rod shaft 520. In some cases, one or more lockout stops may be provided with a continuous spiral shape around the syringe rod shaft 520.

In some cases, the lockout assembly is forward (eg, when the actuator 250 is engaged) when the syringe rod 257 is translated distal to the longitudinal axis of the fluid infusion system (eg, when the actuator 250 is engaged). For example, it translates (toward the distal direction with respect to the vertical axis of the fluid injection system 100). In some cases, the lockout assembly 500 can pass the lockout stop 560 as the lockout assembly translates distally to the vertical axis of the fluid injection system 100. In many cases, the lockout assembly 500 is involved when the lockout assembly is translated proximally to the longitudinal axis of the fluid injection system 100 (eg, when the actuator 250 is engaged and then disengaged). In) one or more lockout stops 560 cannot be passed.

In some cases, the actuation of the volume selector 530 (eg, rotation of the volume selector dial 530) can rotate the syringe rod shaft 520 and the attached lockout stop 560 within the housing of the fluid injection system 100. In some cases, the lockout stop 560 is fixed so that the lockout assembly 500 cannot pass through the lockout stop when translating in the proximal direction to the longitudinal axis of the fluid injection system 100. The injection volume is selected by rotating to position.

A fluid delivery mechanism 280 (eg, one or more fluid delivery rods 280) can be coupled to the lockout assembly 500. In some cases, one or more fluid delivery rods 280 are rigidly attached to the lockout assembly 500. In many cases, one or more fluid delivery rods 280 are coupled to the lockout assembly 500 at the proximal end 282 of one or more fluid delivery rods 280. In many cases, the fluid delivery rod is also prevented when the lockout assembly is prevented from translating proximally within the housing of the fluid injection system 100 (eg, relative to the longitudinal axis of the fluid injection system 100). , (Eg, when the actuator 250 is engaged and then disengaged) is prevented from further translating in the proximal direction with respect to the longitudinal axis of the fluid injection system 100.

The fluid injection system 100 can include a syringe rod spring 510. In some cases, the syringe rod spring 510 (eg, the proximal end of the syringe rod spring 510) can be urged against the syringe rod fixture 258 (eg, the syringe rod pin). In some cases, the syringe rod spring 510 can be urged against the proximal portion of the syringe body 260 and / or the strut joint 256. In some cases, the syringe rod spring 510 is placed in a compressed state between the syringe rod fixture 258 and one or both of the syringe body 260 and the strut joint 256.

In some cases, the spring constant of the syringe rod spring 510 is less than that of the syringe body spring 264. In some cases, a syringe (eg, as supplied by the syringe body spring 264) that exceeds the distally directed force acting on the syringe body 260 (eg, as supplied by the syringe rod spring 510). The proximally directed force acting on the body 260 causes the syringe body 260 to move proximally with respect to the longitudinal axis of the fluid injection system 100, for example as a result of an unbalanced force acting on the syringe body 260. Will make it possible. Syringe rods, for example, in various cases where the lockout assembly 500 or a portion thereof (eg, one or more lockout pins 501) has contacted (eg, engaged) the lockout stop 560. A syringe body spring 264 with a spring constant greater than that of the spring 510 allows the syringe body 260 and syringe rod 257 to move proximally in parallel while the fluid delivery rod 280 and lockout assembly 500 remain in place. There will be. In some cases, this can push the fluid delivery channel 270 over the fluid delivery rod, propelling the fluid from at least a portion of the fluid delivery channel 270 into the target tissue through the fluid delivery member 320. Can bring.

The amount of fluid delivered to the tissue is such that one or more fluid delivery members 320 extend from the distal end 114 of the extension member 110 and / or the actuator 250 is engaged (eg,). It can be related to the degree (pressed). In many cases, the amount of fluid delivered to the tissue may depend directly on the extent to which the actuator 250 is engaged, with one or more fluid delivery members 320 extending from the distal end 114 of the extension member 110. It is directly related to the distance you are in. For example, in some cases, the actuator 250 may be further pushed to engage the lockout pin 501 with a lockout stop 560 located closer to the distal end of the syringe rod shaft 520. .. In many cases, the act of pushing the actuator 250 further extends the fluid delivery member 320 further away from the distal end 114 of the extension member 110. Releasing the actuator 250 pressed to a greater extent also causes the syringe (eg, due to the force exerted by the syringe body spring 264 on the interior of the syringe body 260 and the distal end of the housing of the system 100). A large amount of fluid can also be pushed from the fluid delivery channel 270 by the fluid delivery mechanism 280 (eg, fluid delivery rod 280) as the body 260 moves proximally within the housing of the system 100.

(Extension member)
The system 100 may include an extension member 110 that includes a lumen 112 defined by its inner wall. The lumen 112 may extend along the vertical axis of the extension member 110 or in parallel with it, from the proximal end 113 to the distal end 114 over the entire length of the extension member 110. The extension member 110 may include a hollow tube. For example, the extension member 110 may include a sheath, hypotube shaft, needle, or equivalent. Alternatively, the lumen 112 may extend along any length desired by one of ordinary skill in the art, with any configuration relative to the longitudinal axis of the extension member 110 desired by one of ordinary skill in the art. The distal end of the lumen 112 may correspond to the distal end 114 of the extension member 110 as shown.

The extension member 110 may contain metal. The extension member 110 may include stainless steel, nitinol, conventional thermoplastics used in intervention introducers (eg HDPE, Pebax, etc.), or equivalents, or any combination thereof.

The extension member 110 may include a rigid material. Alternatively or in combination, the extension member 110 may include a flexible material.

FIG. 8 shows a schematic view of the handheld thin fluid injection system 100. The system 100 may include a plurality of fluid delivery members 320 arranged within the extension member 110 as described herein. Each of the plurality of fluid delivery members 320 may include a fluid delivery lumen through which it passes and at least one outlet port 322 at its distal end, as described herein. Each fluid delivery lumen can be fluid independent of all other fluid delivery lumens, as described herein. The plurality of fluid delivery members 320 may have a retracted configuration and an extended configuration as described herein. The system 100 may include one or more fluid delivery channels 270 that are fluidly coupled to the fluid delivery lumen as described herein. In some embodiments, each fluid delivery channel 270 may be fluidly coupled to a single fluid delivery lumen of multiple fluid delivery members 320. For example, in the system 100 with three fluid delivery members 320 as shown, the fluid delivery member 320 and the fluid delivery channel 270 are fluid independent of all other fluid delivery members 320 and the fluid delivery channel 270, respectively. As such, it may have three fluid delivery channels 270 that are fluidly coupled to the fluid delivery member 320. System 100 may include one or more fluid delivery channels 280 as described herein. For example, the system 100 may include three fluid delivery rods 280 as shown, each of which is a single fluid delivery channel (eg, a fluid reservoir) of the three fluid delivery channels (eg, fluid reservoir). For example, it is operably coupled to a fluid reservoir). The three fluid delivery rods 280 may be configured to operate simultaneously or independently of each other, as described herein. The operation of the fluid delivery rod 280 may allow fluid to be delivered from the plurality of fluid delivery channels 270 to the plurality of fluid delivery members 320 out of the outlet port 322 and into the tissue of interest. The system 100 is adjacent to the proximal end of the extension member 110 and is a plurality of fluid delivery members 320 and / or movable bodies for extending or retracting the plurality of fluid delivery members 320 as described herein. An actuator 250 may be provided that is operably coupled to the 160. The fluid delivery rod 280 may be actuated by the actuator 250 to allow simultaneous fluid delivery and retraction of the fluid delivery member 320, as described herein.

The housing of the system 100 may include a handle 170 (eg, a grip) adjacent to the proximal end of the extension member 110. In some embodiments, the fluid delivery channel 270 may be located within the handle 170 as shown. In some embodiments, the fluid delivery channel 270 may be located within or coupled to the syringe body 260 slidably located within the handle 170 or extension member 110.

Alternatively or in combination, the fluid delivery channel 270 is fluidly coupled to the outside of the handle 170, eg, to the proximal end of the handle 170 and / or to the fluid delivery member 320 via a tube, in an external fluid bag. It may be located in.

FIG. 9 shows a cross-sectional view of the extension member 110 of the thin fluid injection system 100. The plurality of fluid delivery members 320 may be arranged within the lumen 112 of the extension member 110 as described herein. The extension member 110 may have an outer diameter 116 that is sized for use as a minimal or non-invasive injection system, as described herein. The inner diameter 118 of the extension member 110 that defines the lumen 112 may determine the size and / or number of fluid delivery members 320 that may be placed therein. For example, the extension member 110 may be an 18G tube having an outer diameter of 116 mm of 1.27 mm and an inner diameter of 118 of 0.84 mm. As many as seven 31G needles with an outer diameter of 324 of 0.26 mm may fit into the lumen 112 of an 18G tube. The plurality of fluid delivery members 320 may have an inner diameter 326 sized to provide fluid delivery, as described herein. The size of the extension member 110 and / or the size of the fluid delivery member 320 may be adjusted as desired to provide the system with the desired contour and / or number of fluid delivery members 320.

In some embodiments, the extension member 110 may comprise a needle, sheath, or tube with a gauge number of about 10 to about 20. The extension member 110 is, for example, within a range bounded by any two of the following gauge numbers: 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20: It may have an outer diameter of 116. The extension member 110 may have, for example, a gauge number of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

The extension member 110 may have an outer diameter 116 of about 0.9 mm to about 3.5 mm. The extension member 110 may have an outer diameter 116 of about 2 mm to about 4 mm. The extension member 110 has the following values, that is, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1 mm. .5mm, 1.6mm, 1.7mm, 1.8mm, 1.9mm, 2mm, 2.1mm, 2.2mm, 2.3mm, 2.4mm, 2.5mm, 2.6mm, 2.7mm, 2 Of 8.8 mm, 2.9 mm, 3 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, or 4 mm. It may have an outer diameter 116 within a range bounded by any two.

The extension member 110 may have an outer diameter 116 of about 3 French to about 10 French. The extension member 110 is, for example, within a range bounded by any two of the following values: 3 French, 4 French, 5 French, 6 French, 7 French, 8 French, 9 French, or 10 French. May have an outer diameter of 116. The extension member 110 may have, for example, an outer diameter 116 of about 3 French, about 4 French, about 5 French, about 6 French, about 7 French, about 8 French, about 9 French, or about 10 French.

The extension member 110 fits within a conventional biopsy access needle, conventional endoscope, conventional laparoscopic system, conventional vascular access sheath, or equivalent work channel, as described herein. It may have an outer diameter 116 that is sized to do so.

The extension member 110 may have a longitudinal length of about 4 cm to about 250 cm. For example, the extension member 110 is 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 11 cm, 12 cm, 13 cm, 14 cm, 15 cm, 16 cm, 17 cm, 18 cm, 19 cm, 20 cm, 1 cm to 20 cm. It may have a length of 4, 4 cm to 20 cm, 5 cm to 15 cm, 7 cm to 13 cm, or 9 cm to 11 cm. Alternatively, the extension member 110 may have a length of about 100 cm to about 250 cm. The extension member 110 has the following values, that is, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 11 cm, 12 cm, 13 cm, 14 cm, 15 cm, 16 cm, 17 cm, 18 cm, 19 cm, 20 cm, 25 cm, 30 cm. , 35 cm, 40 cm, 45 cm, 50 cm, 75 cm, 100 cm, 125 cm, 150 cm, 175 cm, 200 cm, 225 cm, 250 cm, 275 cm, or even having a length within the range bounded by any two of 300 cm. good.

System 100 may be configured for fluid delivery from about 1 cm to about 300 cm remote from a patient access point (eg, mouth, skin surface, rectum, etc.). In some embodiments, the system may be configured for fluid delivery from about 1 cm to about 30 cm below the skin surface. For example, the system may be configured for fluid delivery from about 1 cm to about 4 cm below the skin surface or about 4 cm to about 20 cm below the skin surface. Alternatively, the system may be configured for fluid delivery from about 20 cm to about 40 cm below the skin surface. Alternatively, the system may be configured for fluid delivery from about 100 cm to about 250 cm below the skin surface or from an entry point (eg, mouth) into the body.

The length of the extension member 110 used for a particular application may depend on the location of the tissue site of interest. For example, a system 100 with a longer extension member 110 can be used to deliver one or more agents to a target tissue located deeper inside the subject or tissue.

(Fluid delivery member)
One or more fluid delivery members 320 may be located within the lumen 112 of the extension member 110. For example, four fluid delivery members 320 may be coated with an extension member 110 as shown. Any desired number of fluid delivery members 320 may be housed within the lumen 112 of the extension member 110 as described herein. The fluid delivery member 320 has a distal end, a proximal end, an inner wall defining a fluid delivery lumen therein, and an outlet port 322 at the distal end that is fluidly coupled to the lumen. You may prepare. Each fluid delivery lumen can be fluidly independent of all other fluid delivery lumens. One or more fluid delivery members 320 may include multiple needles or tubes. For example, one or more of the fluid delivery members 320 may include a plurality of pencil tip needles, blunt tip needles, or tilted tip needles.

In some embodiments, each fluid delivery member 320 may be provided with a single outlet port 322 at its distal end, as described herein. In some embodiments, some or all of the plurality of fluid delivery members 320 are described, for example, in PCT / US2008 / 073212, the entire contents of which are incorporated herein by reference. As such, it may be provided with at least one additional outlet port 322 along its exposed length that is fluidly coupled to the fluid delivery lumen.

The fluid delivery member 320 may have a retracted configuration and an extended configuration. The fluid delivery member 320 may remain in a retracted configuration while the system 100 is inserted into the patient's body (eg, through the skin or mouth 701) and positioned in close proximity to the tumor site 702. The fluid delivery member 320 may extend into the tumor 702 to deliver the therapeutic agent to the tumor tissue 702, as shown, extending from the distal end 114 of the extension member 110 to an extending configuration. .. The fluid delivery member 120 may be returned to the retracted configuration for removal of the system 100 from the patient.

The plurality of fluid delivery members 320 may include one or more of metals or plastics. The plurality of fluid delivery members 320 may include shape memory alloys. The fluid delivery member 320 may include stainless steel, nitinol, conventional thermoplastics used in intervention introducers (eg HDPE, Pebax, etc.), or equivalents, or any combination thereof.

The plurality of fluid delivery members 320 may include a flexible material. Alternatively or in combination, the plurality of fluid delivery members 320 comprises a rigid material.

In some embodiments, the fluid delivery member 320 may comprise a needle, sheath, or tube with a gauge number in the range of about 28 to about 33. One or more fluid delivery members 320 may be 25 gauge needles. In some cases, the fluid delivery member 120 is 20 gauge, 21 gauge, 22 gauge, 23 gauge, 24 gauge, 26 gauge, 27 gauge, 28 gauge, 29 gauge, 30 gauge, 31 gauge, 32 gauge, or 33 gauge. It may be equipped with a needle. The fluid delivery member 320 may have, for example, the following gauge numbers, i.e., an outer diameter 124 within a range bounded by any two of 28, 29, 30, 31, 32, or 33. .. One or more of the fluid delivery members may have, for example, a gauge number of 28, 29, 30, 31, 32, or 33.

The fluid delivery member 320 may have an outer diameter of 324 in the range of about 0.05 mm to about 0.5 mm. The fluid delivery member 320 has the following values, that is, 0.05 mm, 0.06 mm, 0.07 mm, 0.08 mm, 0.09 mm, 0.1 mm, 0.15 mm, 0.2 mm, 0.25 mm, 0. It may have an outer diameter of 324 within a range bounded by any two of 3 mm, 0.35 mm, 0.4 mm, 0.45 mm, or 0.5 mm. One or more of the fluid delivery members 120 are about 0.05 mm, about 0.06 mm, about 0.07 mm, about 0.08 mm, about 0.09 mm, about 0.1 mm, about 0.15 mm. May have an outer diameter of 324 of about 0.2 mm, about 0.25 mm, about 0.3 mm, about 0.35 mm, about 0.4 mm, about 0.45 mm, or about 0.5 mm.

The system 100 may include one or more fluid delivery members 320 that are located within the lumen 112 of the extension member 110. The system 100 may include, for example, a plurality of fluid delivery members 320. The plurality of fluid delivery members 320 may include at least two fluid delivery members 320. The plurality of fluid delivery members 320 may include 2 to 20 fluid delivery members 320. The plurality of fluid delivery members 320 have the following values: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, Alternatively, a number of fluid delivery members 320 may be provided within a range bounded by any two of the twenty.

FIG. 10A shows a schematic view of a thin fluid injection system 100 with a fluid delivery member 320 in a retracted configuration. FIG. 10B shows a system 100 with a fluid delivery member 320 in an extended configuration. The system 100 may include a plurality of fluid delivery members 320 arranged within the extension member 110, as described herein. Each of the plurality of fluid delivery members 320 may include a fluid delivery lumen and at least one outlet port 322 at its distal end, as described herein. Each fluid delivery lumen can be fluid independent of all other fluid delivery lumens, as described herein. The plurality of fluid delivery members 320 may have a retracted configuration and an extended configuration as described herein.

The fluid delivery member 320 may be configured to be completely encapsulated in the lumen 112 of the extension member 110 in a retracted configuration. In some cases, the plurality of fluid delivery members 320 may each extend from the distal end 114 of the extension member 110 to the proximal end of the extension member 110. For example, the length of each of the plurality of fluid delivery members 320 may be substantially similar to the length of the extension member 110.

Each of the plurality of fluid delivery members 320 may have a length in the range of about 4 cm to about 250 cm. For example, the plurality of fluid delivery members 320 may each have a length in the range of about 4 cm to about 20 cm. Alternatively, the plurality of fluid delivery members 320 may each have a length in the range of about 100 cm to about 250 cm. The plurality of fluid delivery members 320 have, for example, the following values, that is, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 11 cm, 12 cm, 13 cm, 14 cm, 15 cm, 16 cm, 17 cm, 18 cm, 19 cm, 20 cm, respectively. , 25 cm, 30 cm, 35 cm, 40 cm, 45 cm, 50 cm, 75 cm, 100 cm, 125 cm, 150 cm, 175 cm, 200 cm, 225 cm, 250 cm, 275 cm, or 300 cm. You may have.

The length of the fluid delivery member 320 may be adjusted depending on the length of the extension member 110 and / or the location of the tissue site of interest.

The fluid delivery member 320 may extend outward from the distal end 114 of the extension member 110 to an extension configuration, as described herein. In the extending configuration, each of the plurality of fluid delivery members 320 may be angled away from the vertical axis 111 of the extension member 110.

In some embodiments, the distal end 114 of the extension member 110 is positioned to guide a plurality of fluid delivery members 320 and angle them away from the longitudinal axis 111 of the extension member 110 in an extending configuration. It may include one or more angular elements 115 (eg, a magnifying mechanism). The angular element or expansion mechanism may include, for example, one or more channels or guides within the extension member 110 that preferentially guide the plurality of fluid delivery members 320 to the desired expansion configuration.

Alternatively or in combination, at least the distal end of each of the plurality of fluid delivery members 320 is an extension of the plurality of fluid delivery members 320 from the distal end 114 of the extension member 110 of the plurality of fluid delivery members 320. Each distal exposed end may include a shape memory material or compressible material to allow self-expansion in a separation pattern.

In the extending configuration, each of the plurality of fluid delivery members 320 may be angled at an oblique angle away from the vertical axis 111 of the extension member 110. Each of the plurality of fluid delivery members 320 may be angled away from the vertical axis 111 of the extension member 110 at an angle within the range of about 10 ° to about 90 ° (eg, spread angle). One or more of the plurality of fluid delivery members 320 has the following values: 10 °, 15 °, 20 °, 25 °, 30 °, 35 °, 40 °, 45 °, 50 ° , 55 °, 60 °, 65 °, 70 °, 75 °, 80 °, 85 °, or 90 ° from the vertical axis 111 of the extension member 110 at an angle 329 within a range bounded by any two. It may be angled so that it separates. For example, one or more of the fluid delivery members 120 (eg, when extending from the distal end 114 of the extension member 110 outside the biological tissue, or the biological tissue). It may be angled away from the vertical axis 111 of the extension member 110 at an angle of 329 of 10 ° to 45 °, 15 ° to 30 °, or 20 ° to 25 ° (when extending inward of).

In the extending configuration, each of the plurality of fluid delivery members 320 has an extension member 110 such that the distance 321 between the respective distal ends of the plurality of fluid delivery members 320 is in the range of about 1 mm to about 10 mm. It may be angled away from the vertical axis 111. Each of the plurality of fluid delivery members 320 has a distance 321 between the distal ends of the plurality of fluid delivery members 320 having the following values, that is, 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm. The extension member 110 may be angled away from the vertical axis 111 so that it is within a range bounded by any two of 9 mm or 10 mm.

In the extension configuration, each of the plurality of fluid delivery members 320 may have a length of 323 extending outward from the distal end 114 of the extension member 110. The length 323 of each of the plurality of fluid delivery members 320 extending outward from the distal end 114 of the extension member 110 in the extension configuration is in the range of about 1 mm to about 50 mm, eg, about 5 mm to about 40 mm. Can be within range. The length 323 of each of the plurality of fluid delivery members 320 extending outward from the distal end 114 of the extension member 110 in the extension configuration has the following values, namely 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 10 mm. , 15 mm, 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, or 50 mm, which may be within the range bounded by any two.

(Fluid delivery channel)
System 100 may include one or more fluid delivery channels 270 (eg, fluid reservoirs) that are fluidly coupled to the fluid delivery lumen. In some embodiments, each fluid delivery channel 270 is fluidly coupled to a single fluid delivery lumen of multiple fluid delivery members 320. For example, in the system 100 with three fluid delivery members 320 as shown, the fluid delivery member 320 and the fluid delivery channel 270 are fluid independent of all other fluid delivery members 320 and the fluid delivery channel 270, respectively. As such, it may have three fluid delivery channels 270 that are fluidly coupled to the fluid delivery member 320. Alternatively, one or more fluid channels 270 or parts thereof may be fluidly coupled to more than one fluid delivery member 320, respectively. For example, one fluid delivery channel 270 may be fluidly coupled to two fluid delivery members 320. Alternatively or in combination, one or more fluid delivery members 320 are fluidly coupled to more than one fluid delivery channel 270, for example when fluid mixing is desired within the fluid delivery member 320. May be done. For example, one fluid delivery member 320 may be fluidly coupled to two fluid delivery channels 270 to mix two different fluids together within the fluid delivery member 320 during injection.

In some embodiments, the fluid delivery channel 270 may be loaded with fluid prior to inserting the distal end 114 of the extension member 110 into the body. Alternatively, or in combination, the fluid delivery channel 270 may be loaded with fluid during or after inserting the distal end 114 of the extension member 110 into the body.

In some embodiments, the fluid delivery channel 270 may be directly coupled to the proximal end of the fluid delivery member 320.

In some embodiments, the fluid delivery channel 270 is not directly coupled to the proximal end of the fluid delivery member 320, but may be fluidly coupled.

In some embodiments, the plurality of fluid delivery channels 270 may comprise fluid delivery lumens of multiple fluid delivery members 320. For example, the plurality of fluid delivery channels 270 may be loaded with the fluid into the plurality of fluid delivery channels 270, and the fluid may be loaded (or primed) into the fluid delivery lumen. It may be directly and openly coupled to the fluid delivery lumen of member 320. In some embodiments, the fluid delivery lumen of the plurality of fluid delivery members 320 may be a plurality of fluid delivery channels 270. That is, the plurality of fluid delivery channels 270 may consist of the fluid delivery lumens of the plurality of fluid delivery members 320, and the fluid may be loaded directly into the fluid delivery lumens.

In some embodiments, the plurality of fluid delivery channels 270 may include multiple cartridges as described herein.

Each of the plurality of fluid delivery channels 270 may have a volume in the range of about 10 μl to about 500 μl (ie, retain the volume of fluid within it). The plurality of fluid delivery channels 270 have the following values, for example: 10 μl, 20 μl, 30 μl, 40 μl, 50 μl, 60 μl, 70 μl, 80 μl, 90 μl, 100 μl, 125 μl, 150 μl, 175 μl, 200 μl, 225 μl, 250 μl, 275 μl, respectively. , 300 μl, 325 μl, 350 μl, 375 μl, 400 μl, 425 μl, 450 μl, 475 μl, or 500 μl.

The volume of each fluid delivery channel 270 can vary depending on the length of the extension member 110 as the fluid is "primed" within the entire fluid path prior to use, and each fluid fluidly coupled to it. The volume of the delivery member lumen may be provided.

In some embodiments, the system 100 is fluidly coupled to one or more of the fluid delivery lumens, or one or more of the fluid delivery channels 270. One or more labeled reservoirs (eg, one or more cartridges 432) may be provided. For example, each fluid delivery member 320 (eg, each fluid delivery lumen of each fluid delivery member 320) or fluid delivery channel 270 fluidly into a labeled reservoir (eg, cartridge 432) holding a labeling agent therein. It may be combined. In some cases, each cartridge 432 (eg, each labeled reservoir) may be fluid independent of all other cartridges 432 (eg, labeled reservoir). System 100 is one of fluid delivery channels 270 or connected fluid delivery cavities such that the fluid injected into the tissue contains both a labeling agent and a therapeutic agent within the same injection column. Among those above that, the labeling and therapeutic agents may be configured to be mixed. In some cases, mixing may occur prior to infusion of the therapeutic agent. In some cases, mixing may occur during injection of the therapeutic agent.

FIG. 11A shows three exemplary prototype thin fluid injection systems 100 with three fluid delivery members 320 in a retracted configuration. FIG. 11B shows a system 100 with a fluid delivery member 320 in an extended configuration. The fluid injection system 100 is shown next to a dime for full size comparison. Three systems 100 were formed using thin extension members 110 having gauge numbers of 18, 16 and 14 (from left to right in FIGS. 12A and 12B, respectively). In the retracted configuration, the three fluid delivery members 320 were completely encapsulated within the extension member 110 of each system 100. In the extension configuration, the three fluid delivery members 320 extend outward from the distal end 114 of the extension member 110 at an angle away from the longitudinal axis 111 of the extension member 110 of each system 100, as described herein. rice field.

FIG. 12A shows a prototype of an exemplary thin fluid injection system 100 with three fluid delivery members 320 in a retracted configuration. FIG. 12B shows a system 100 with a fluid delivery member 320 in an extended configuration. The fluid injection system 100 is shown next to a dime for full size comparison. In the retracted configuration, the three fluid delivery members 320 were completely encapsulated within the extension member 110. In the extension configuration, the three fluid delivery members 320 extend outward from the distal end 114 of the extension member 110 at an angle away from the longitudinal axis 111 of the extension member 110, as described herein.

FIG. 13A shows a schematic top view of the subcutaneous tumor tissue 702 following injection using the thin fluid injection system 100. FIG. 13B shows a perspective view of the injection column 704 created following injection using the thin fluid injection system 100. System 100 is a discretely mapped location (ie, drug) of one or more agents (eg, drugs) for the user to observe a spatially defined tumor response to the drug at the injection site 703. , Injection site) may be configured to be injected into the tissue at 703. The agent may be injected into the tissue in a uniform column-like orbital 704 through the z-axis of the tissue, as shown in FIG. 13B. In some cases, the agent can be injected into the tissue within a column that is parallel to each other. In some cases, the agent can be injected into the tissue within a column that is not parallel to each other (eg, as shown in FIG. 13C). For example, within a column in which one or more agents are aligned with one or more fluid delivery members (eg, when the fluid delivery member is in an extended (eg, spread) configuration). Can be injected into the tissue with. One or more agents are injected into the tumor with a label as described herein to aid in the identification of drug candidates and / or to confirm successful drug delivery. You may.

The system 100 may be configured to inject a plurality of fluids at a plurality of injection sites 703 to form a plurality of injection columns 704 within the tissue. In some embodiments, the fluid delivery members 320 differ so that the number of distinctly different agents / fluids injected into the tumor is the same as the number of fluid delivery members 320 / injection site 703. A fluid / agonist may be injected. In other embodiments, one or more fluid delivery members 320 such that the number of distinctly different agents / fluids injected into the tumor is less than the number of fluid delivery members 320 / injection site 703. May be injected with the same fluid / agonist. Alternatively or in combination, one or more of the fluid delivery members 320 may be injected with the same active ingredient but at different concentrations of fluid / agonist.

The drug may be left in the tumor 702 for a pre-determined cycle prior to excision and analysis, eg, about 24 hours to about 72 hours. During that time, the drug may diffuse into the tissue directly surrounding the infusion column 704. The infusion column 704 produced by the system 100 may be separated in a manner that prevents secondary contamination or allows the drug to mix within the tissue, as desired by one of ordinary skill in the art. ..

Tissue 702 may be resected for therapeutic efficacy and / or toxicity analysis of the drug. Assessing the therapeutic efficacy of a drug is known, for example, in cytotoxicity, hypoxia, angiogenesis, immune response, targeted biochemistry or dysregulation of genetic pathways, or equivalents, or any combination thereof. For markers, it may include analyzing tissue 702.

Tissue 702 may be sampled at multiple tumor depths to assess the consistency of tumor response to the drug, which is particularly useful for heterologous tumor types with spatially variable microenvironments. obtain. The resected tissue is cut into multiple contiguous sections, for example, at pre-determined intervals along the injection column, and any known histology, histology, immunohistochemistry, immunohistochemistry known to those skilled in the art. , Histological pathology, microscopy, cytology, biochemistry, pharmacology, molecular biology, immunochemistry, imaging, or other analytical techniques, or a combination thereof.

FIG. 14 shows a schematic view of the thin fluid injection system 100. System 100 is used to deliver one or more agents, eg, therapeutic agents or drugs, through skin 701 or other access points (eg, mouth), eg, to internal target tissue 702 in a subcutaneous tumor. May be done.

FIG. 15A shows the distal end of an exemplary thin fluid infusion system 100 with an angular element and three fluid delivery members 320 in an unextended (eg, retracted) configuration adjacent to simulated tumor tissue 702a. show. The simulated tumor tissue 702a contained a 0.55% agarose gel stained with a red food colorant inside the test tube. The distal end 114 of the extension member 110 was positioned adjacent to the simulated tumor tissue 702a. Three fluid delivery members 320 were then extended into the simulated tumor tissue 702a. As shown in FIG. 15B, the fluid delivery member 320 was normally extended into the tumor tissue simulated at an oblique angle. As disclosed herein, the actuator 250 can be engaged with the fluid delivery member 320 in an extending configuration, as shown in FIG. 15B. FIG. 15C shows system 100 during simultaneous infusion of fluid into simulated tumor tissue 702a and simultaneous retraction of fluid delivery member 320. The fluid delivery member 320 retracts at a rate of 0.75 mm / sec while each microliter of fluid containing 50% green food colorant is injected into the simulated tumor tissue 702a. rice field. Simultaneous injection and retraction resulted in a clear injection column 702 within the simulated tumor tissue 702a.

(Fluid delivery mechanism)
System 100 may include one or more fluid delivery mechanisms 280. In many cases, the fluid delivery mechanism can include a fluid delivery rod 280. The fluid delivery mechanism can include a plurality of fluid delivery rods 280. The operation of the fluid delivery rod 280 may allow fluid to be delivered from the plurality of fluid delivery channels 270 to the plurality of fluid delivery members 320 out of the outlet port 322 and into the tissue of interest.

In some embodiments, the fluid delivery mechanism 280 is capable of operating each of the plurality of fluid delivery channels 270 such that the actuation of the fluid delivery rod 280 simultaneously delivers fluid from each of the plurality of fluid delivery members 320. A single fluid delivery rod 280 to be coupled may be provided.

Alternatively, the fluid delivery mechanism 280 may include multiple fluid delivery rods. In some embodiments, the plurality of fluid delivery rods 280 are each operably coupled to a single fluid delivery channel 270 (eg, fluid reservoir) of the plurality of fluid delivery channels 270 (eg, fluid reservoir). You may. In some embodiments, the plurality of fluid delivery rods 280 are independent of each other so that each of the plurality of fluid delivery members 320 can deliver fluid independently of all other fluid delivery members 320. It may work. In some embodiments, the plurality of fluid delivery rods 280 are each capable of operating on a fluid delivery channel 270 (eg, one fluid reservoir) that exceeds one of the plurality of fluid delivery channels (eg, fluid reservoir). It may be combined.

The fluid delivery mechanism 280 may include a mechanical actuator or an electromechanical actuator. In some embodiments, the fluid delivery rod 280 may comprise one or more of a plunger or pump. In some embodiments, the fluid delivery rod 280 comprises a gasket (eg, a rubber gasket or a plastic gasket). For example, the fluid delivery rod 280 may be provided with a gasket at its distal end, which may be configured to form a watertight junction with the medial side surface (eg, inner wall surface) of the fluid delivery channel. In some cases, the fluid delivery rod 280 does not include a gasket. In many embodiments, the fluid delivery rod 280 is configured to slide through a fluid channel (eg, fluid delivery channel) or reservoir. Moving the fluid delivery rod 280 within the fluid channel or reservoir (eg, sliding the fluid delivery rod 280 through the fluid delivery channel or reservoir) can move the fluid within the fluid delivery channel or reservoir. For example, moving the fluid delivery rod 280 distally to the fluid delivery channel or reservoir can move the fluid in the fluid delivery channel or reservoir distally within the fluid delivery channel or reservoir. In some cases, moving the fluid delivery channel or reservoir proximal to the fluid delivery rod 280 can move the fluid in the fluid delivery channel or reservoir distally to the fluid delivery channel or reservoir. can. The diameter of the fluid delivery rod 280 is such that when the fluid delivery rod 280 is moved relative to the fluid delivery channel 270 or reservoir, the fluid in the fluid delivery channel 270 or reservoir is moved so that the fluid delivery channel 270 or reservoir is moved. Can be sized relative to the inner diameter of the.

The fluid delivery rod 280 may be operated manually. Alternatively or in combination, the fluid delivery rod 280 may be automatically operated, for example, by a computer program as described herein.

FIG. 16A shows a schematic view of a thin fluid injection system 100 prior to fluid injection with a fluid delivery member 320 in an unextended configuration. In some cases, the actuator 250 can be engaged to extend one or more fluid delivery members 320 (eg, as shown in FIG. 16B) into the tissue 702. In some cases, the extent to which the actuator 250 is engaged determines the distance the fluid delivery member 320 extends within the tissue 702. The fluid delivery member 320 can retract into the fluid injection system (eg, into the extension member 110), as shown in FIG. 16C. In some cases, the retraction of the fluid delivery member 320 is the result of passively (eg, due to the action of a spring inside the system 100) or pulling the actuator 250 back to its initial position (eg, due to its initial position). As active).

FIG. 16D shows a schematic view of a thin fluid injection system 100 prior to fluid injection with a fluid delivery member 320 in an extended configuration. FIG. 16E shows the system 100 after simultaneous fluid injection and retreat of the fluid delivery member 320. The system 100 may include a plurality of fluid delivery members 320 arranged within the extension member 110, as described herein. Each of the plurality of fluid delivery members 320 may include a fluid delivery lumen through which it passes and at least one outlet port 322 at its distal end, as described herein. Each fluid delivery lumen can be fluid independent of all other fluid delivery lumens, as described herein. The plurality of fluid delivery members 320 may have a retracted configuration and an extended configuration as described herein. The system 100 may include one or more fluid delivery channels 270 that are fluidly coupled to the fluid delivery lumen as described herein. In some embodiments, each fluid delivery channel 270 may be fluidly coupled to a single fluid delivery lumen of multiple fluid delivery members 120. For example, in the system 100 with three fluid delivery members 320 as shown, the fluid delivery member 320 and the fluid delivery channel 270 are fluid independent of all other fluid delivery members 320 and the fluid delivery channel 270, respectively. As such, it may have three fluid delivery channels 270 that are fluidly coupled to the fluid delivery member 320. System 100 may include one or more fluid delivery channels 280 as described herein. For example, the system 100 may include three fluid delivery rods 280 as shown, each of which is a single fluid delivery channel 270 of the three fluid delivery channels (eg, fluid reservoir). It is operably coupled to (eg, fluid reservoir 130). The three fluid delivery rods 280 may be configured to operate simultaneously or independently of each other, as described herein. The operation of the fluid delivery rod 280 may allow fluid to be delivered from the plurality of fluid delivery channels 270 to the plurality of fluid delivery members 320 out of the outlet port 322 and into the tissue of interest.

(Actuator)
The system 100 is operably coupled to a plurality of fluid delivery members 320 and / or syringe bodies 260 operably coupled thereto, adjacent to the proximal end of the extension member 110 and as described herein. The actuator 250 (for example, the expansion actuator 250) may be provided. The actuator 250 can stay at an angle of 259 with respect to the vertical axis 101 of the fluid injection system 100 when the actuator is not engaged. In certain embodiments, the actuator angle 259 can be 10 degrees to 180 degrees, 10 degrees to 90 degrees, 30 degrees to 90 degrees, 30 degrees to 60 degrees, or 30 degrees to 45 degrees. In some cases, the actuator angle 259 can be an angle around the actuator hinge 251. In some cases, the actuator angle 259 can be measured with respect to a plane parallel to the vertical axis 101 of the fluid injection system 100. For example, the actuator angle 259 can be measured with respect to a plane parallel to the vertical axis 101 extending through the actuator hinge 251.

Actuator 250 may shift a plurality of fluid delivery members 320 from a retracted configuration to an extended configuration or from an extended configuration to a retracted configuration. The actuator 250 may include a mechanical actuator or an electromechanical actuator.

Actuator 250 may be operated manually. Alternatively or in combination, the actuator 250 may be automatically operated, for example, by a computer program as described herein.

In some embodiments, the fluid delivery rod 280 may be actuated by the actuator 250 to allow simultaneous fluid delivery and retraction of the fluid delivery member 320, as described herein. Alternatively or in combination, the fluid delivery rod 280 may be operated independently by the actuator 250.

The actuation of the fluid delivery rod 280 acts on the plurality of fluid delivery members 320 and / or the syringe body 260 of the system 100 so that the fluid delivery occurs at the same time as the retreat of the fluid delivery member 320 from the extending configuration to the retracting configuration. It may be combined as possible. The plurality of fluid delivery members 320 may be configured to retract from the extending configuration to the retracting configuration at the same time as the fluid delivery from the fluid delivery member 320. Simultaneous fluid delivery and retraction of the fluid delivery member 320 may aid in the formation of a clean injection column 704 within the tissue of interest (as shown in FIG. 9).

Simultaneous fluid delivery and retreat of the fluid delivery member 320 can be achieved by "pulling" the fluid delivery channel 270 and the fluid delivery member 320 towards the steady fluid delivery rod 280 within the body of the system 100. The fluid delivery channel 270 may be, for example, slidably located within an extension member 110 or handle or equivalent, operably coupled to, or located inside, a syringe body 260 of system 100. The retreat of the fluid delivery member 320 from the extending configuration (shown in FIG. 16D) to the retreating configuration (shown in FIG. 9) engages the steady fluid delivery rod 280 and causes the fluid to flow from the fluid delivery channel 270 to the fluid delivery member. A step of retracting the syringe body 260 and the fluid delivery channel 270 located therein may be included from the distal position to the proximal position in order to flow to the distal end of the 320 and drain from the outlet port 322. This mechanism of action contrasts with a conventional plunger syringe-like mechanism in which the fluid delivery rod is "pushed" into a stationary fluid delivery reservoir (eg, fluid delivery channel 270) located within the body of the system. obtain.

Simultaneous fluid delivery or retreat of the fluid delivery member 320 can be achieved by electromechanical means. For example, the coordinating gear may retract the fluid delivery member 320, while the micropump may inject fluid from the fluid delivery member 320.

The actuator 250 may be configured to retract a plurality of fluid delivery members 320 from an extended configuration to a retracted configuration at the same speed. Alternatively, the actuator 250 exceeds one or more of a plurality of fluid delivery members 320 at different speeds, eg, to maintain the same fluid delivery volume per area for fluids of different viscosities or flow rates. It may be configured to retract things.

The fluid delivery member 320 may be retracted at a rate sufficient to generate the injection column 704, as described herein.

The fluid delivery member 320 may be retracted at a speed in the range of about 0.1 mm / sec to about 10 mm / sec. For example, the speed has the following values: about 0.1 mm / sec, about 0.2 mm / sec, about 0.3 mm / sec, about 0.5 mm / sec, about 1 mm / sec, about 2 mm / sec, about. Bounded by any two of 3 mm / sec, about 4 mm / sec, about 5 mm / sec, about 6 mm / sec, about 7 mm / sec, about 8 mm / sec, about 9 mm / sec, or about 10 mm / sec. It may be within the range.

Each fluid delivery channel 270 may hold the same volume of fluid. Alternatively, one or more of the fluid delivery channels 270 may hold different volumes of fluid.

Each of the plurality of fluid channels 270 may have a volume in the range of about 10 μl to about 500 μl. For example, the volume of fluid channel 270 has the following values: about 10 μl, about 20 μl, about 30 μl, about 40 μl, about 50 μl, about 75 μl, about 100 μl, about 150 μl, about 200 μl, about 250 μl, about 300 μl, about 350 μl. , About 400 μl, about 450 μl, or may be within the range bounded by any two of about 500 μl.

The fluid delivery lumens of the plurality of fluid delivery members 320 may each hold the same volume of fluid. Alternatively, one or more of the fluid delivery lumens of the plurality of fluid delivery members 320 may hold different volumes of fluid.

The fluid delivery lumens of the plurality of fluid delivery members 320 may each have a volume in the range of about 0.1 μl to about 10 μl. For example, the volume of the fluid delivery member lumen has the following values: about 0.1 μl, about 0.2 μl, about 0.3 μl, about 0.5 μl, about 1 μl, about 2 μl, about 3 μl, about 4 μl, about It may be within the range bounded by any two of 5 μl, about 6 μl, about 7 μl, about 8 μl, about 9 μl, or about 10 μl.

Each volume of the fluid delivery lumen may depend on the length of the extension tube 110 and the length of its corresponding fluid delivery member 320, which may vary depending on the location of the tissue site of interest.

The fluid delivery rod 280 has a flow rate sufficient to generate the injection column 704, as described herein, with the generation of minimal shear and the induction of mechanical chemical damage to the tissue 702. The fluid may be configured to be delivered out of the outlet port 322.

The fluid delivery rod 280 may be configured to deliver fluid out of the outlet port 322 at a flow rate in the range of about 0.1 μl / sec to about 10 μl / sec. For example, the flow rate has the following values: about 0.1 μl / sec, about 0.2 μl / sec, about 0.3 μl / sec, about 0.5 μl / sec, about 1 μl / sec, about 2 μl / sec, Bounded by any two of about 3 μl / sec, about 4 μl / sec, about 5 μl / sec, about 6 μl / sec, about 7 μl / sec, about 8 μl / sec, about 9 μl / sec, or about 10 μl / sec. It may be within the range.

(Volume selector)
18A and 18B show a fluid injection system 100 with a volume selector 530. Often, the volume selector 530 is used to control the volume of fluid injected into the target tissue. The volume selector 530 can be located at the proximal end of the fluid injection system 100. The volume selector 530 can be coupled (eg, rigidly coupled) to the volume adjusting screw 540. The volume control screw 540 can be coupled to the syringe rod shaft 520. In some cases, activating (eg, rotating) the volume selector 530 activates the syringe rod shaft 520 (eg, rotating the syringe rod shaft 520 around the vertical axis 101 of the fluid injection system 100). be able to. In some cases, the volume selector 530 comprises a dial. In some cases, the volume selector 530 can be used to set the volume to be injected into the target tissue by rotating the dial to a selected volume position. In some cases, the volume selector 530 can be used to select the volume to be injected from a plurality of discrete volumes. In some cases, a volume selector can be used to select a volume from a continuous range of volumes. In some embodiments, the volume selector 530 is 1 microliter to 1.5 microliter, 1.5 microliter to 2.0 microliter, 2.0 microliter to 2.5 microliter, 2.5 microl. Lt to 3.0 microliter, 3.0 microliter to 3.5 microliter, 3.5 microliter to 4.0 microliter, 4.0 microliter to 4.5 microliter, 4.5 microliter to 5.0 microliters, 5.0 microliters to 5.5 microliters, 5.5 microliters to 6.0 microliters, 6.0 microliters to 6.5 microliters, 6.5 microliters to 7. 0 microliter, 7.0 microliter to 7.5 microliter, 7.5 microliter to 8.0 microliter, 8.0 microliter to 8.5 microliter, 8.5 microliter to 9.0 micro Lit, 9.0 microliter to 9.5 microliter, 9.5 microliter to 10.0 microliter, 10.0 microliter to 50.0 microliter, 50.0 microliter to 100.0 microliter, It can be used to set the volume for injections from 100.0 microliters to 500.0 microliters, or greater than 500.0 microliters. In some cases, activating the volume selector 530 may activate one or more lockout stops of the fluid injection system 100. In some cases, activating one or more lockout stops of the fluid injection system 100 may include a step of rotating the syringe rod shaft 520 (eg, a step of rotating the syringe rod shaft 520). Includes the step of rotating one or more lockout stops 560 to a position for engaging the lockout assembly 500). As disclosed herein, the selected volume is the distance that one or more fluid delivery members 320 extend from the distal end 114 of the extension member 110 when the actuator 250 is engaged. Can be related to. For example, using the volume selector 530 to select a larger volume for delivery, one or more fluid delivery members 320 are distal to the extension member 110 when the actuator 250 is engaged. The distance extending from the end 114 can be increased. The volume selector 530 may include one or more volume setting indicators 550. The volume setting indicator 550 can include one or more visual and / or tactile features. In some cases, one or more visual and / or tactile features can comprise information about possible injection volume settings.

(Distal cap)
Turning to FIGS. 19A and 19B, the fluid infusion system 100 can include a distal cap 600. Distal caps can be useful in preventing accidental leakage of fluids (eg, agents) provided by the fluid infusion system 100. One or more fluids to be delivered to the target tissue can be harmful if allowed to contact non-target tissue (eg, the skin of the subject or the skin of a bystander). In some cases, the distal cap 600 can prevent accidental contact of fluid with one or more of the fluid infusion systems 100 with non-target tissue. The distal cap 600 can include one or more cap reservoirs 620. In some cases, the cap reservoir 620 of the distal cap 600 may be useful for collecting fluid from the distal end 328 of one or more fluid delivery members 320. The distal cap 600 can also help determine if one or more channels, openings (eg, openings), or reservoirs of system 100 are clogged and will impede fluid flow. It can help ensure that one or more channels and / or reservoirs of the fluid injection system 100 are fully filled (eg, to prevent incomplete filling). For example, the fluid delivery member 320 of one or more of the fluid infusion system 100 fills one or more channels and / or reservoirs of one or more of the fluid infusion system 100 with one or more of the distal caps 600. Can be immersed in a fluid containing one or more agents contained in the insertion reservoir 630 greater than or equal to. Loading the fluid infusion system 100 from the distal cap 600 is also useful in reducing the volume of liquid and / or solid agents to be delivered to (eg, infused into) the tissue. could be.

The distal cap 600 can include a cap insert 610. The cap insert 610 can include one or more cap reservoirs 620. In some cases, the cap inserts 610 are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 pieces, 10-20 pieces, 20-30 pieces, 30-40 pieces, 40-50 pieces. It comprises, or more than 50, cap reservoirs 620. The cap reservoir 620 of the cap insert 610 is 0.1 microliter to 10 microliter, 10 microliter to 20 microliter, 20 microliter to 50 microliter, 50 microliter to 100 microliter, 100 microliter to 200 micro. It can have fluid volumes greater than liters, 200 microliters to 500 microliters, 500 microliters to 1,000 microliters, or 1,000 microliters.

The distal cap 600 can include an insert receptor 630. In various embodiments, the cap insert 610 and insert receptor are capped, for example, while the cap insert 610 and insert receiver 630 are respectively seated on the distal end 114 of the extension member 110. The insert is configured so that it can be fitted inside the insert receptor 630. In some cases, the inner diameter of the distal portion of the insert receptor 630 is identical to the outer diameter 650 of the distal portion of the cap insert 610. In some cases, the inner diameter of the distal portion of the insert receiver 630 is 0.1 mm to 0.2 mm, 0.2 mm to 0.5 mm, 0. 5 mm to 1.0 mm, 1.0 mm to 5.0 mm, or 5.0 mm larger. The distal end of the insert receptor 630 is 0.5 mm to 1.0 mm, 1.0 mm to 2.0 mm, 2.0 mm to 3.0 mm, 3.0 mm to 4.0 mm, 4.0 mm to 5.0 mm. , 5.0 mm to 6.0 mm, 6.0 mm to 7.0 mm, or can have an outer diameter of 670 larger than 7.0 mm.

The insert receptor 630 can include one or more receptor notches 640. The receptor notch 640 can be, for example, a cutout feature of the insert receptor 630 located on the distal edge of the insert receptor 630. In some cases, the receptor notch 640 may be useful in removing the cap insert 610 from the insert receptor 630. For example, a cap insert 610 with a distal end that is flush with the distal end of the insert receptor 630 contacts the cap insert 610 in the space created by the receptor notch 640 and receives the insert. It can be removed from the insert receptor 630 by guiding the cap insert 610 out of the container 630. In some cases, the cap insert 610 is an extension member without removing the insert receptor 630 from the distal end 114 (eg, when the used cap insert has been replaced with a different cap insert). It can be removed from the distal end 114 of 110.

The distal cap can include a proximal end 602 and a distal end 604. In some cases, the proximal end 602 of the distal cap 600 is shaped to receive the distal end 114 of the extension member 100. The proximal end 602 of the distal cap 600 can have an inner diameter 660 equal to or slightly larger than the outer diameter of the distal end 114 of the extension member 110. In some cases, the distal end 114 of the extension member 110 has a structural feature configured to retain the distal cap over the distal end of the extension member 110. For example, the distal end 114 of the extension member 110 can comprise a recess that is shaped to mesh with a hole edge or fastening mechanism on the proximal end 602 of the distal cap 600.

The distal cap 600 is used to fill (eg, load) at least a portion of the fluid infusion system 100 with one or more fluids containing one or more agents. be able to.

(cartridge)
Turning to FIGS. 20A and 20B, the thin fluid injection system 100 may include a cartridge 432. The cartridge 132 may be removable from the fluid injection system 100. The cartridge 432 can include a cartridge shell 470. In some cases, the cartridge 132 is disposable. In some cases, the cartridge 432 is reusable. Cartridge 432 or one or more portions thereof may be pressure sterilized. The fluid injection system 100, which comprises a removable and / or reusable cartridge 432, can have improved versatility. For example, one or more cartridges 432 to be used with the fluid injection system 100 can be prepared in advance. In some cases, one or more cartridges 432 can be remotely prepared and shipped or shipped to the location where they will be used. The thin fluid injection system 100, which comprises one or more cartridges 432, also (eg, by substituting and / or rearranging one or more cartridges 432 used in the fluid injection system). It can also be easily reconfigured from the first injection configuration to the second injection configuration.

Cartridge 432 may be fully or partially filled with fluid prior to being inserted or loaded into chamber 400. The cartridge 432 may be prefilled by a technician or pharmacist before the cartridge 432 is loaded into the chamber of device 100. In some cases, the prefilled cartridge 432 can be stored, shipped, or frozen. Alternatively or in combination, the cartridge 432 may be loaded with fluid after being inserted or loaded into chamber 400. For example, the cartridge 432 may be loaded with a fluorescent label prior to being inserted into chamber 400, followed by a drug compound after being inserted into chamber 400.

Cartridges are preloaded with one or more agents (eg, one or more therapeutic agents, one or more indicators, and / or one or more buffers or excipients). May be done. In some embodiments, the cartridge 432 may be preloaded with one or more indicators (eg, markers). Alternatively or in combination, the cartridge 432 may be preloaded with one or more therapeutic compounds.

The cartridge 432 can include a cartridge stopper 450. The cartridge stopper 450 can include one or more of a variety of materials useful for capping the vial. Cartridge stoppers can include polymers or copolymers. The cartridge stopper 450 can include natural rubber or synthetic rubber (eg, butyl rubber). In some cases, the cartridge stopper 450 comprises a self-healing material (eg, a material capable of maintaining a watertight seal after being punctured). In some cases, the cartridge 432 can be loaded by injecting one or more fluids (eg, one or more agents) through the cartridge stopper 450.

In some cases, the cartridge 432 further comprises a stopper seal 460. In some cases, the stopper seal 460 holds the cartridge stopper 450 in place at the end of the cartridge 432 (eg, the proximal end 432b) and / or (eg, the cartridge stopper in the end of the cartridge 432). It is configured to assist in maintaining a watertight seal at the end of the cartridge 432). The stopper seal 460 can include a metal, polymer, copolymer, or ceramic material. In some cases, the stopper seal 460 is a crimp seal.

The cartridge 432 can include a cartridge plunger 440. In some cases, the cartridge plunger 440 is slidably inserted or positioned in a longitudinal position inside the cartridge 432. For example, the cartridge plunger can be positioned vertically inside the cartridge 432, closer to the distal end 432a of the cartridge 432 than to the proximal end 432b of the cartridge 432. In some cases, the cartridge plunger 440 may inject one or more fluids through the cartridge stopper 450, for example, so that the cartridge 432 has one or more fluids (eg, one or more agents). ) Is loaded, it is translated distally along the vertical axis of the cartridge 432. The cartridge plunger 440 can include a plunger interface 442. In some cases, the plunger interface 442 can include a material that can be punctured by a needle (eg, a self-healing material). In some cases, the plunger interface 442 comprises a mechanism configured to allow fluid communication of the contents of the cartridge 432 with a fluid delivery channel 270, such as a port configured to engage the delivery channel interface 290. Can be done.

The cartridge 432 may include one or more cartridge reservoirs configured to hold a volume of fluid 480. In some cases, the cartridge 432 comprises a plurality of cartridge reservoirs. In some cases, two or more of the plurality of cartridge reservoirs in the cartridge 432 can communicate with each other in fluid communication. For example, the pressure applied to the cartridge plunger 440 (eg, when the cartridge 432 is loaded into the chamber 400 of the fluid injection system 100) mixes the contents of the cartridge reservoir with two or more of the cartridges 432. Can be made to.

The various cartridges 432 disclosed herein may be configured to hold a volume of fluid 480 (eg, by slidingly inserting a cartridge plunger 440). The cartridge 432 can be configured to hold a specific volume of fluid by changing the position of the cartridge plunger 440. In some cases, the cartridge 432 is 1 microliter to 500 microliter, 10 microliter to 500 microliter, 100 microliter to 500 microliter, 200 microliter to 500 microliter, 300 microliter to 500 microliter, 1 Microliter to 250 microliter, 1 microliter to 100 microliter, 1 microliter to 50 microliter, 1 microliter to 40 microliter, 1 microliter to 30 microliter, 1 microliter to 20 microliter, 1 microliter 10 microliters, 1 microliter to 9 microliters, 1.25 microliters to 9 microliters, 2 microliters to 8 microliters, 3 microliters to 7 microliters, 3.75 microliters to 6.5 microliters It is configured to hold a volume of 4, 4 microliters to 6 microliters, or 0.1 microliters to 1 microliter. The volume of the cartridge 432 depends on any two of the following values: about 1 μl, about 2 μl, about 3 μl, about 4 μl, about 5 μl, about 6 μl, about 7 μl, about 8 μl, about 9 μl, or about 10 μl. It may be within the bounded range. The plurality of cartridges 432 of the fluid injection system 100 may each hold the same volume of fluid. Alternatively, one or more of the plurality of cartridges 432 may hold different volumes of fluid.

The cartridge 432 has 2.0 mm to 3.0 mm, 3.0 mm to 4.0 mm, 4.0 mm to 5.0 mm, 5.0 mm to 6.0 mm, 6.0 mm to 7.0 mm, 7.0 mm to 8. It can have an outer diameter larger than 0 mm, 8.0 mm to 9.0 mm, 9.0 mm to 10.0 mm, or 10.0 mm. Cartridge 432 is less than 1.0 mm, 1.0 mm to 2.0 mm, 2.0 mm to 3.0 mm, 3.0 mm to 4.0 mm, 4.0 mm to 5.0 mm, 5.0 mm to 6.0 mm, 6 It can have an inner diameter larger than 0.0 mm to 7.0 mm, 7.0 mm to 8.0 mm, 8.0 mm to 9.0 mm, 9.0 mm to 10.0 mm, or 10.0 mm.

The cartridge 432 may be configured to be inserted into a correspondingly formed recess or chamber 400 within the housing of the fluid injection system 100. In some cases, the cartridge 432 can be held in place by the cartridge retention device 430 after being loaded into the chamber 400 of the fluid injection system 100. The cartridge retention device 430 may include various structural elements for holding the cartridge 432 in place (eg, during use of the fluid injection system 100). For example, the cartridge retention device 430 may include a spring mechanism for urging the cartridge 432 against the chamber 400 and / or the cartridge abutment 410. In many cases, the cartridge retention device 430 includes a clip for holding the cartridge 432 in place within the chamber 400. The cartridge retention device 430 may include a hole edge formed to fit across the proximal end 432b of the cartridge 432 when the cartridge 432 is pressed against the cartridge abutment 410. A typical embodiment of the cartridge retention device 430 includes a hole edge as shown in FIG. 4B.

In some cases, positioning the cartridge 432 within the chamber 400 (eg, by engaging the cartridge 432 with the cartridge retainer 430) may cause the cartridge abutment 410 to apply compressive force to the cartridge plunger 440. can. In some cases, the force applied to the cartridge plunger 440 (eg, by the cartridge abutment 410) can cause pressurization of the fluid 480 inside the cartridge 432. In some cases, pressurization of the fluid 480 inside the cartridge 432 allows the fluid 480 to flow from the cartridge 432 into the fluid delivery channel 270 (eg, via the cartridge interface 420). In some embodiments, the cartridge 432 may be coupled directly to the proximal end of the fluid delivery member 320 (eg, when the cartridge 432 is engaged with the cartridge retention device 430).

In some embodiments, the cartridge 432 may be loaded with fluid prior to inserting the distal end 114 of the extension member 110 into the body. Alternatively or in combination, the cartridge 432 may be loaded with fluid during or after inserting the distal end 114 of the extension member 110 into the body.

In some embodiments, the cartridge 432 may be loaded into the system 100 prior to inserting the distal end 114 of the extension member 110 into the body. Alternatively or in combination, the cartridge 432 may be loaded into the system 100 during or after inserting the distal end 114 of the extension member 110 into the body.

In some embodiments, one or more of the cartridges 432 may include labeled reservoirs as described herein. One or more cartridges 432 may hold, for example, a labeling agent therein. One or more cartridges 432 are such that the fluid injected into the tissue mixes the labeling agent and the therapeutic agent in the same injection column so that it contains both the labeling agent and the therapeutic agent. It may be configured in. In some cases, mixing may occur prior to infusion of the therapeutic agent. In some cases, mixing may occur during injection of the therapeutic agent.

(Acting substance)
The fluid 480 of the cartridge 432 can contain one or more agents. One or more agents of fluid 480 can be therapeutic agents. For example, fluid 480 can contain one or more drugs, such as antitumor drugs. In some cases, fluid 480 comprises a plurality of agents. In some cases, fluid 480 comprises a plurality of therapeutic agents. In many cases, the two cartridges 432 of the fluid injection system 100 include different agents or different combinations of agents.

In some cases, one or more agents of fluid 480 can be diagnostic agents. For example, fluid 480 can include indicator agents. Indicator agents can include fluorescent dyes, color dyes, or credit markers.

One or more agents of fluid 480 can include fluorescence tracking molecules. The fluorescence tracking molecule can help track the area of the target tissue that is contacted by the fluid 480 injected into the target tissue (eg, using the fluid injection system 100). Importantly, the use of fluorescent tracking molecules within the fluid injection system 100 is to determine the relative location and / or orientation of the target tissue, for example, during a second time point or after explantation of the target tissue. Can assist.

The fluorescence tracking molecule can be fine particles. The fluorescence tracking molecule can be a fluorescence tracking microsphere (FTM). For example, the fluorescence tracking molecule can be a polymer microsphere. The fluorescence tracking molecule can include polystyrene. In some cases, polystyrene can provide performance benefits during the data acquisition and analysis steps. For example, polystyrene is commonly used in histological processes and can adversely affect certain polymers and / or leached dyes from indicator molecules, including various other materials, imaging infused tissue such as xylene. And show resistance to harsh chemicals that can be used during analysis. In some cases, tissue treatment can be performed with aliphatic hydrocarbons (eg, Clear-Rite ^TM 3) to improve dye retention of FTM particles. Crosslinkers can be used to improve the chemical thermal resistance properties of FTM particles. For example, FTM particles can include DVB crosslinked polystyrene. DVB crosslinkers can be used at concentrations of 0.1% to 5% during FTM particle formation. In some cases, the fluorescence tracking microspheres (FTM) can include benzoguanamine formaldehyde resin. In some cases, fluorescence tracking microspheres can provide benefits for allowing microspheres to be sectioned using common sectioning practices. In such situations, it is possible that microspheres are dragged across the tissue, which are injected during the process of sectioning, which can cause tissue tearing and / or displacement of particles to each other or to tissue. It can be low in sex.

The advantage of the fluid infusion system 100, which includes a fluorescence tracking microsphere (FTM), is that it tracks one or more agents and / or fluids that are precisely delivered to the tissue, and damages the tissue, or FTM. Includes the ability to treat tissues containing one or more FTMs without causing a significant adverse effect on the brightness of the. In addition, FTM retains excellent brightness and visibility within the tissue, even when FTM is formulated with relatively small amounts of dye.

FTMs can be delivered to multiple sites 703 within tissue 702 using a fluid infusion system such as System 100 disclosed herein, and one or more FTMs (eg, one or more) Detected in tissue 702 prior to tissue excision (as shown in FIGS. 21A-21D). One in the tissue, even if the injected tissue has been moved or even healed by using a radiation source 800, such as a visible or ultraviolet light source (eg, in the form of a handheld device). It is possible to determine the location, orientation, and / or boundary of one or more injection sites 703 beyond that. In many cases, the use of FTM in such situations does not require a special detector, at least because the FTM can be easily imaged using a handheld radiation source (eg, in many cases). Tests (eg, immunohistochemistry, with or without antibody use) performed on the tissue after delivery of the follow-up particles (eg, after excision of the tissue) because they can be visually identified when imaged). Compatible with no fluorescence imaging, and in-situ hybridization), rather than both the use of metal-based implants and the use of inking in combination with imaging methods (eg, fluorescence fluoroscopy, ultrasound, or computed tomography). Are better. Therefore, the use of FTM particles is large and expensive because, for example, FTM particles can be quickly and intuitively imaged and evaluated using a smaller (eg, handheld) radiation source such as handheld ultraviolet light. The need for equipment can be reduced or eliminated. The lights and filters used to illuminate and detect the injection site are compact and handheld, and large fluorescence used in surgical settings to detect metal reference markers placed within the tumor during the biopsy and excision process. Compared to fluoroscopes, it can enable quick and economical detection.

Other examples of injection devices, systems, and methods that can be used in conjunction with FTM include US Pat. Nos. US8,349,554, US8,657,786, US8,834,428, US8,475. , 412, US8,672,887, US8,926,567, US9,205,201, and US9,205,202 (as a whole herein for all purposes). Includes those disclosed in). Methods using FTM disclosed herein are also described in US Pat. Nos. 8,349,554, US8,657,786, US8,834,428, US8,475,412, No. Disclosures in US8,672,887, US8,926,567, US9,205,201, and US9,205,202 (incorporated herein as a whole for all purposes). It can also be applied to other devices, systems, and methods, such as those that are used.

It may be advantageous to control the size of the fluorescence tracking microspheres (FTM) to be delivered to the tissue. For example, particles larger than 100 nanometers resist post-injection migration, which can be due to changes in local fluid pressure, diffusion, and / or tissue deformation. Particles with a diameter of 5 micrometers or smaller may be less likely to be phagocytosed by cells in the injected tissue. Fluorescence tracing molecules are 0.1 micrometer to 1.0 micrometer, 1.0 micrometer to 5.0 micrometer, 5.0 micrometer to 10.0 micrometer, 4.0 micrometer to 11.0. It can be micrometer, 4.0 micrometer to 12.0 micrometer, or 1.0 micrometer to 20.0 micrometer. Often, the multiple FTM particles to be delivered to the tissue (eg, loaded into a cartridge or distal cap, or located within the fluid delivery channel or reservoir of System 100) are 0.1%. ~ 1.0%, 1.0% ~ 2.0%, 2.0% ~ 3.0%, 3.0% ~ 4.0%, 4.0% ~ 5.0%, or 5.0 % To 10.0% C.I. V. It can have a diameter within the range. In some cases, the first cartridge 432 or fluid delivery channel 270 may comprise an FTM population having a first diameter, and the second cartridge or fluid delivery channel 270 may have a second diameter. FTM population can be provided. In some cases, the first set of agents to be delivered to the tissue with the first population of FTM is the relative or absolute size (eg, diameter) of the first and second populations of FTM. ) And / or signals (eg, radiofluorescence wavelengths) can be differentiated from a second set of agents that should be delivered to the tissue with a second population of FTMs. Therefore, it is possible to generate many clearly identifiable FTM populations using a relatively small number of optical brighteners, which may require fewer fluorescent imaging channels of the detector to distinguish. For example, two diameters of FTM particles and two different dyes are used to generate six uniquely identifiable FTM particle populations (eg, using either a single dye or both dyes). It is possible. Fluorescence tracking microspheres (eg, sized to 5.0 micrometers to 10.0 micrometers) are small enough to travel with the fluid injected into the target tissue and can be phagocytosed. The lower the value is, the smaller the value is, and the more the tissue analysis and, if applicable, the more likely it is to remain localized during the treatment, the greater the value.

Fluorescence tracking microspheres (FTM) can include dyes. For example, FTM particles can include polymeric microspheres that are dyed with one or more dyes. The fluorescence tracking molecule can include an organic dye. The organic dye of the fluorescence tracking molecule can be a fluorescent organic dye. In some cases, aqueous dyes such as aqueous UV dyes can be used with FTM particles, however, organic dyes are excellent in many applications due to the low tendency of fine particles to seep out in the aqueous environment. There is. FTMs are dyes in the range of 0.1% to 0.4%, 0.01% to 1%, or 0.1% to 5% (% by weight by weight) weight content per bead (eg, fluorescent dyes). Can be formulated to include. In some cases, the fluorescence tracking molecule can have an excitation wavelength of 450 nm to 495 nm or 300 nm to 600 nm. Dyes that can be used with FTM (eg, incorporated into FTM particles) are Nile Red, Yellow 160, BODIPY dyes, Lucifer Yellow, xanthene derivatives (eg, fluorescein, fluorescein isothiocyanate (FITC), rodamine, tetramethyllodamine). (TRITC), Oregon Green, Eosin, Texas Red), Cyanine Derivatives (eg Cy2, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy7, Cyanine Indocarbocyanine, Oxazine Carbocyanine, Thiacarbocianine, Melocinin ), Squaline Derivatives, Squaline Rotaxane Derivatives, Naphthalene Derivatives, Cumarin Derivatives, Oxazine Zole Derivatives (eg, Pyridyloxazole, Nitrobenzoxazine, Benzoxaziazole), Anthracene Derivatives, Pyrene Derivatives (eg Cascade Blue) , Oxazine derivatives (Nile Red, Nile Blue, Cresyl Violet, Oxazine 170, etc.), aclysine derivatives, allylmethine derivatives, or tetrapyrrole derivatives can be included. In some cases, each cartridge 432 comprising the fluid injection system 100 can have a different detection wavelength or detection wavelength range. The dye of the FTM particles can generate a detectable signal (eg, in response to excitation by a radiation source such as a visible light lamp or ultraviolet light). In some cases, the signal from the FTM particles can be detected using one or more detectors. In some cases, the signal from the FTM particle is visually assessed (eg, by a surgeon, engineer, nurse, histologist, researcher, or other scientist). The signal from the FTM particles (eg, from the dye of the FTM particles) can be 350 nm to 750 nm, 400 nm to 600 nm, 450 nm to 550 nm, 400 nm to 500 nm, 500 nm to 600 nm, greater than 750 nm, or less than 350 nm.

In many cases, the fluid injection system 100 can be loaded with FTM particles containing different dyes or combinations of dyes. For example, a set of dyes in which the first fluid delivery member differs from or greater than the second population of FTM particles loaded into or used by the second fluid delivery member. Can be used to load and / or deliver a first FTM population, including. Therefore, the first set of one or more agents to be delivered from the first fluid delivery member to the tissue is one or more agents to be delivered from the second delivery member to the tissue. Can be differentiated from the second set of.

Due to the strong activation of fluorescence tracking microspheres, FTM is 0.1% -5%, 5% -10%, 10%, 10% -20%, 20% -30%, 30% -40%, It can be added to the drug for delivery to the tissue at a concentration of 40% to 50%, or greater than 50%. In some cases, FTM (eg, polystyrene FTM) is 35 milliliters / milliliter (mg / ml) to 45 mg / ml, 25 mg / ml to 50 mg / ml, 15 mg / ml to 60 mg / ml, 10 mg / ml to 65 mg / ml. In a fluid (eg, with one or more agents) to be delivered to the tissue in excess of ml, 0.01 mg / ml to 1 mg / ml, 1 mg / ml to 10 mg / ml, or 60 mg / ml. ) Can be formulated. In some cases, formulation of FTM in fluid for delivery in the range of 10 mg / ml to 50 mg / ml provides the best brightness and density of FTM particles.

One or more agents of the fluid injection system 100 can be implantable agents. For example, one or more agents comprising System 100 or delivered to tissue using System 100 are implantable agents such as implants configured for controlled release of the substance. obtain. Implantable agents can include pellets, powders, slurries, or microdevices. In some cases, the implantable agent can include an injectable micropump. In some cases, the implantable agent can include a degradable matrix, such as a degradable polymer matrix. Implantable agents can be configured to deliver (eg, release) one or more agents (eg, drugs) into the tissue during and / or after injection. In some cases, one agent can be delivered to the tissue by an implantable agent. In some cases, multiple agents can be delivered to the tissue by an implantable agent. Implantable agents delivered by System 100 can include bioabsorbable materials.

Implantable agents (eg, degradable polymer particles or micropumps) may be configured to release one or more agents into the tissue at a constant rate or at a variable rate. can. In some cases, the rate of release of one or more agents into the tissue by the implantable agent can increase over time. In some cases, the rate of release of one or more agents into the tissue by the implantable agent can decrease over time. In some cases, the release rate of one or more agents into the tissue by the implantable agent can both increase and decrease over time. In some cases, control of the release rate of the agent into the tissue by the implantable agent may cause the degradable particles to have a larger or smaller amount of the agent at different locations within the implantable agent. Composition of implantable agents by engineering design and / or (eg, by selecting the type or ratio of one or more polymers or copolymers, including various parts of the implantable agent). It can be accomplished by the choice of and / or the various distribution of agents to be delivered through the implantable agent. The use of implantable agents can be advantageous for controlling tissue exposure to one or more agents.

In some cases, the implantable agent can be, for example, a reference marker for marking a location within a tissue. For example, implantable agents may include one or more pellet or tablet-shaped implants that can be delivered to the tissue through one or more fluid delivery members 320 to mark the injection site. can. In some cases, the implantable agent containing the reference marker can include a metal or a metal alloy. In some cases, the implantable agent containing the reference marker may be detectable using an electromagnetic field and / or using a radiation source or visual inspection.

(Use)
The devices, systems, and methods described herein may be used for the delivery of any agent to solid tissue for therapeutic or non-therapeutic purposes.

The devices, systems, and methods described herein may be used for preclinical drug development and testing and / or clinical drug development and testing.

The devices, systems, and methods described herein are for personalized medical use, eg, to determine the most effective therapeutic agent or agent combination for tumor treatment of an individual patient. May be used for.

The devices, systems, and methods described herein may be used to access a target site within the body and deliver one or more fluids therein. The target site may be, for example, about 1 cm to about 300 cm away from the patient access point (eg, mouth, skin surface, rectum, etc.). The target site may be located, for example, about 1 cm to about 30 cm below the skin surface. The target sites are, for example, 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 11 cm, 12 cm, 13 cm, 14 cm, 15 cm, 16 cm, 17 cm, 18 cm, 19 cm, 20 cm, 1 cm on the skin surface. It may be located at ~ 20 cm, 5 cm to 15 cm, 7 cm to 13 cm, or 9 cm to 11 cm below. The target site may be located, for example, about 4 cm to about 20 cm below the skin surface. The target site may be, for example, at a distance of about 100 cm to about 250 cm from the patient access site.

The target site may be, for example, a superficial target site that can be accessed transdermally, eg, at a depth of about 0.2 cm to about 4 cm in a human patient.

The target site may be, for example, an intermediate target site that can be accessed transdermally, eg, at a depth of about 4 cm to about 20 cm in a human patient.

The target site is, for example, endoscopically or interveningly, at a deeper target site that can be accessed, eg, about 100 cm to about 250 cm deep from the entry point in a human patient (eg, from the mouth to the stomach). There may be.

In some cases, the target site may be a tumor. The tumor may be located anywhere in the patient's body. Tumors include, for example, the patient's skin, breast, brain, prostate, colon, rectum, kidney, pancreas, lung, liver, heart, stomach, intestine, ovary, testis, cervix, lymph nodes, thyroid, esophagus, head. Alternatively, it may be located in the cervix, eyes, bones, or bladder. The tumor may be located anywhere in the body where a solid tumor is found.

Tumors that can be treated using the devices, systems, and methods described herein are, but are not limited to, gastric cancer, esophageal cancer, liver metastases from colon cancer, papillary renal cell carcinoma, head and neck cancer, thyroid. Cancer, ovarian cancer, cervical cancer, lymphoma, skin cancer (eg, melanoma), pancreatic cancer, prostate cancer, testicular cancer, renal cell cancer, breast cancer, colon cancer, brain cancer (eg, medullary blastoma, collagen bud) Includes cell tumors, etc.), lung cancers (eg, mesenteric tumors, small cell lung cancers, non-small cell lung cancers, etc.), liver cancers (eg, hepatocellular carcinomas, etc.), bladder cancers, rhombic myomas, and osteosarcoma.

The devices, systems, and methods described herein may be used to deliver one or more therapeutic agents to the tissue of interest. Therapeutic agents may be delivered in liquid form. Exemplary therapeutic agents for the treatment of cancer are, but are not limited to, common chemotherapeutic agents, bisphosphonates, hormone therapies, antibodies, immunotherapies (eg, CART cells, NK cells, etc.), steroids, blood vessels. Includes formation inhibitors, proteasome / protease inhibitors, tyrosine kinase inhibitors, interferons, interleukins, and equivalents, and any combination thereof.

The devices, systems, and methods described herein may be used to deliver one or more labels (also referred to herein as tags or probes). The label may be delivered with another agent, eg, a therapeutic agent, or as a single agent. The label may be delivered with another agent, eg, conjugated to a therapeutic agent, or with another agent (unbound) in solution. Labels can assist in the detection of injection sites or columns using conventional imaging techniques as described herein and known to those of skill in the art. Exemplary labels include, but are not limited to, fluorescent labels, radioactive labels, gas chromatography / mass spectrometry (GCMS) tags, chemically inert visible injection tracking dyes (ITDs), and equivalents, and combinations thereof. ..

(Method)
FIG. 17 shows a method 1700 of injecting fluid into a tumor in a patient's body using a fluid infusion system 100 as described herein. The method may use one or more of the systems and devices described herein.

In step 1701, a fluid injection system may be provided. The fluid injection system may be any of the fluid injection systems 100 described herein. The fluid injection system comprises, for example, an extension member, a plurality of fluid delivery members disposed therein, and a plurality of fluid reservoirs (eg, fluid delivery channels) fluidly coupled to the plurality of fluid delivery members. You may. A plurality of fluid reservoirs (eg, fluid delivery channels) may each be coupled to a single fluid delivery member, each fluid delivery member being fluidly independent of all other fluid delivery members.

The step of providing the fluid injection system 100 (eg, as in step 1701) can include the step of providing a cartridge 432, such as those disclosed herein. The cartridge 432 can be loaded into the fluid injection system 100. For example, the cartridge 432 can be loaded into the fluid injection system 100. In many cases, the cartridge 432 is loaded into the chamber 400 of the fluid infusion system 100. Loading the cartridge 432 into the fluid injection system 100 involves a chamber 400 with a distal end 432a of the cartridge 432 oriented closer to the distal end 114 of the extension member 110 than the proximal end 432b of the cartridge 432. The step of sliding the cartridge 432 can be included. Loading the cartridge 432 can include contacting the cartridge abutment 410 with the cartridge plunger 440. In some cases, loading the cartridge 432 into the fluid injection system 100 involves engaging the cartridge 432 or a portion thereof (eg, the cartridge plunger 440 or the plunger interface 442) with the cartridge interface 420. The step of engaging the cartridge 432 or a portion thereof with the cartridge interface 420 can include the step of releasably engaging the cartridge 432 with the cartridge interface 420. For example, the cartridge 432 or a portion thereof (eg, the cartridge plunger 440 or the plunger interface 442) is punctured by the cartridge interface 420 (eg, the cartridge interface 420 comprises a needle or pointed channel), or of the cartridge interface 420. Can be screwed onto the threads. Steps to engage cartridge 432 or part thereof with cartridge interface 420 (eg, via delivery channel 270, which can extend through cartridge interface 420 and / or cartridge abutment 410) Fluid 480 contained within cartridge 432. A step of achieving a fluid connection between the and one or more fluid delivery members 320 can be included. Representative examples of loading cartridge 432 into system 100 are shown in FIGS. 4A and 4B.

In step 1702, at least a portion of the fluid infusion system 100 (eg, extension member 110 or portion thereof) may be inserted into tissue (eg, including a portion of the subject's body). The dimensions of the extension member 100 (eg, as disclosed herein) may be contraindicated for minimally invasive interventions (eg, tumors are inoperable, and / or systemic interventions are acute immune responses, etc.) Allows the use of the fluid injection system 100 in applications (which can lead to adverse effects). The insertion may occur with one or more fluid delivery members 320 (eg, retracted into the extension member 110 of the system 100) in an unexpanded configuration. In some cases, at least a portion of the fluid infusion system 100 such that a disposable or pressure sterilizable coaxial sheath allows, for example, multiple uses of the system 100 (eg, at different insertion points of the subject's body). May be positioned around the extension member 110 prior to insertion into the tissue. In some cases, the coaxial sheath can be moored to the fluid injection system 100 by connecting at least a portion of the coaxial sheath to the distal coupling portion 190.

In step 1703, the distal end of the fluid infusion system may be located at or near the target tissue (eg, a tumor or part of the patient's body). The system may be positioned, for example, as the extension member 110 is in close proximity to, for example, touching the target tissue of interest. The step of positioning the system may include, for example, the step of positioning the system under the guidance of the imaging system, for example, using an ultrasound or fluoroscopic imaging system.

In step 1704, one or more fluid delivery members 320 may extend from the distal end 114 of the extension member 110 into the target tissue (eg, tumor tissue). The extension of the fluid delivery member 320 may be actuated by an actuator 250, which may include a mechanical actuator and / or an electromechanical actuator. Actuators can include, for example, thumbwheels, levels, electric actuators, or equivalents. Actuator operation can be automatic or manual. The fluid delivery member may be configured to extend outward from the distal end of the extension member with a pre-determined pattern or curvature. The fluid delivery member may be configured to be angled away from the vertical axis 111 of the extension member 110. The fluid delivery member may be configured to be angled away from the vertical axis 111 of the extension member 110, for example, at an oblique angle of one or more with respect to the vertical axis.

In step 1705, the fluid may be injected into the tumor via a fluid delivery member. As disclosed herein, injecting fluid into the target tumor tissue through a fluid delivery member can include the step of engaging and disengaging the actuator 250. In some cases, the step of injecting the fluid into the tumor tissue (eg, step 1705) can also include the step of retracting the fluid delivery member back into the stretch member (eg, step 1706). .. For example, some embodiments of the fluid injection system 100 can allow simultaneous injection of fluid and removal of fluid delivery members.

In step 1706, the fluid delivery member may be retracted from the tumor into the extension member. As disclosed herein, the fluid delivery member can be retracted (eg, to an unextended configuration) when the actuator 250 is engaged and disengaged.

In step 1707, the fluid infusion system may be removed from the patient's body.

At step 1708, the tumor may be resected for analysis. The tumor may be resected immediately after fluid infusion. Tumors may be resected within 4 hours of fluid infusion, eg, 4-24 hours, 4-48 hours, 6-24 hours, or 4-8 hours. The tumor may be resected within a few days of fluid infusion, eg, about 1 to about 7 days. Tumor tissue may be analyzed as described herein. For example, tumor tissue may be analyzed to determine the effectiveness of one or more combinations of therapeutic agents or agents on the tumor.

The above steps show a method 1700 of injecting fluid into a tumor in a patient's body using a fluid infusion system according to an embodiment, but many variations based on this teaching are described herein. Will be done. The steps may be completed in a different order. Steps may be added or removed. Some of the steps may include substeps. Many of the steps may be repeated as often as useful or necessary for the desired procedure.

For example, in some embodiments, steps 1705 and 1706 optionally allow the fluid to be injected into the tumor while the fluid delivery member is slowly retracted back into the extension member. , May occur at the same time. Simultaneous infusion and retraction can aid in the formation of infusion columns, for example, as shown in FIGS. 15A-15C and as described herein.

In some embodiments, one or more of the steps of Method 1700 may be used for fluid infusion into in vitro or in vitro tissue. In such embodiments, steps 1702, 1707, and 1708 may be optional in certain embodiments of the methods disclosed herein.

Turning to FIG. 21A-21D, the method disclosed herein was delivered (eg, injected therein) to the tissue prior to any excision or explantation of the injected tissue 1 It can include steps to detect and / or evaluate one or more agents. The method disclosed herein inserts at least one fluid delivery member 320 into tissue 702, which can be the tissue of interest, such as a target tissue containing a tumor (eg, as shown in FIG. 21A). Can include steps, including steps. The methods disclosed herein include steps that include delivering (eg, injecting) one or more agents into tissue 702 (eg, as shown in FIG. 21B). be able to. Optionally, the methods disclosed herein allow time to elapse, eg, allow one or more agents delivered to tissue 702 to diffuse or flow through tissue. And / or can include a step that allows one or more agents (eg, as shown in FIG. 21C) to affect tissue 702. The radiation source 800 can be used to detect one or more agents delivered to tissue 702 (eg, as shown in FIG. 21D) (eg, via illumination). For example, the exact location 703 of one or more sites where one or more agents have been delivered to the tissue can be determined quickly and precisely by using the radiation device 800. .. In some cases, the ability to detect one or more agents delivered to tissue 702 is based on, for example, the distribution of one or more agents as determined by imaging tissue 702. , Can help determine the tissue or portion of tissue to be excised (eg, for analysis). In addition to or instead of the radiation source 702, the magnetic detector is to detect and / or evaluate one or more agents delivered to tissue 702 (eg, agents containing a magnetic tag). Although it can be used, the radiation source allows a more precise determination of the spatial distribution of the agent and can be used in combination with a non-magnetic agent (eg, a dye agent and / or a fluorescent agent). However, it will be understood by those skilled in the art.

The radiation source 800 can include an ultraviolet (UV) light source, a visible light source, an infrared illuminator, or a coherent light source. The source 800 is a handheld emitter of a handheld source or a larger source that can allow detection and / or evaluation of agents (eg, FTM particles) prior to or during excision or explantation procedures. could be. In some cases, detectors such as cameras or fluorescence detectors can be used to detect signals of one or more agents delivered to tissue 702. In many cases, one or more agents delivered to the tissue (optionally, radiation source 800) are selected so that signals from one or more agents are visible to the naked eye. Will be. For example, FTM particles can be detected using radiation source 800 prior to excision or explantation of tissue from the subject (eg, as disclosed herein).

The steps shown in FIGS. 21A-21D are representative examples of steps that may be included in the methods disclosed herein. Some methods disclosed herein do not include all the steps shown in FIGS. 21A-21D, and some methods disclosed herein are additional not shown in the figure. It may include steps. For example, the methods disclosed herein may include the step of detecting one or more agents in tissue 702 (eg, one or more fluorescent particles).

(system)
In some embodiments, the system 100 is a handheld system. Alternatively or in combination, the system 100 may be configured for robot control and operation, eg, using instructions from a computer-readable program as described herein.

In some embodiments, the system 100 may be configured as a stand-alone access device for use in accessing a tissue site of interest, such as tumor tissue or a portion thereof. The fluid infusion system 100 can be configured as a stand-alone access device, comprising an extension member 110 configured to puncture the skin of interest and / or penetrate internal tissue (eg, target tissue such as cancer tissue). , One of the various embodiments of the fluid injection system 100 disclosed herein. In some cases, a system configured to be a stand-alone access device can include rounded or pointed ends that can be useful for puncturing or separating biological tissue. In some cases, the system configured to be a stand-alone access device is a needle for injection within, through, or around the tissue (eg, one or more fluid delivery members 320). Can be provided with a rigid extension member that can be useful for manipulating or directing.

In some embodiments, the system 100 may be configured to be used in combination with conventional non- or minimally invasive surgical access devices and introducers known to those of skill in the art. For example, the extension member 110 is externally sized to fit within a conventional biopsy access needle, conventional endoscope, conventional laparoscopic system, conventional vascular access sheath, or equivalent work channel. It may have a diameter. System 100 may be inserted into the working lumen of a conventional access device to reach the tissue of interest. The versatility of the fluid injection system 100, disclosed herein for use with existing access devices and needles, allows practitioners to perform fluid injection as they perform the techniques and tests described herein. Limit training that may require familiarity with the use of System 100.

Alternatively, or in combination, the system 100 may further include its own introducer to provide access to the tumor site of interest. For example, the system 100 may include an introducer sheath for puncturing or penetrating tissue. The system 100 introducer may be coaxial with the axis of the system 100 (eg, the vertical axis) or the axis of a component of the system 100, such as the extension member 110 (eg, the vertical axis). In some cases, the system 100 introducer is separated from the system 100 enclosure and / or other components of the system 100 such as the system 100 extension member 110. The introducer can be used to create a route to the target tissue (eg, by inserting the introducer into the tissue of interest). In some cases, the introducer is used to create a route to the target tissue before another component of the system 100, such as the extension member 110, is inserted into the target tissue and / or any intervening tissue. used. In some cases, the introducer can be coupled to the distal coupling 190 of the system 100 (eg, the distal coupling 190 comprises a luer lock coupling component).

The devices, systems, and methods described herein may be used in conjunction with an imaging system for perioperative imaging of a fluid infusion system in use. Perioperative imaging is a retraction and removal of the infusion system 100 from the patient during fluid delivery, during the insertion and positioning of the system 100 adjacent to the tumor, prior to the insertion of the system 100 into the patient. Imaging of the tumor may be included in between and / or after removal of the system 100. The imaging system may be any imaging system known to those skilled in the art. For example, the imaging system includes an ultrasonic imaging system, an ultrasonic biomicroscopy (UBM) system, an X-ray imaging system, a fluorescence imaging system, an optical coherence tomography (OCT) imaging system, and a magnetic resonance (MR) known to those skilled in the art. ) It may be an imaging system, or any other imaging system.

The systems or methods disclosed herein may comprise a computer or its use. For example, one or more steps of Method 1700 (or other method steps disclosed or necessarily implied herein) are performed by a fully or partially automated system equipped with a computer. May be good. In some cases, the fluid injection system 100 includes a computer. In some cases, the fluid injection system 100 comprises an imaging system (eg, to assist in the insertion, installation, and / or operation of the system). The computer can include a processor (eg, a controller). A computer, when executed, may be provided with instructions that may cause one or more components of the system to perform one or more steps of the methods disclosed herein. Can be equipped with computer-readable memory. In some cases, the operation of the system depends wholly or partially on one or more user inputs.

Preferred embodiments of the present invention are set forth and described herein, but it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Here, a number of variations, modifications, and substitutions will be recalled to those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the invention described herein may be adopted in practicing the invention. The following claims define the scope of the invention, and it is intended that the methods and structures within the scope of these claims and their equivalents are covered thereby.

Claims (120)

It ’s a fluid injection system,
An extension member having a proximal end and a distal end with an inner wall defining a lumen therein.
A plurality of fluid delivery members arranged in the lumen of the extension member and having a retracting configuration and an extension configuration, wherein the plurality of fluid delivery members are distal ends of the extension member in the extension configuration. Configured to extend out from
Each of the plurality of fluid delivery members comprises a distal end, a proximal end, an outlet port at the distal end, and an inner wall defining a fluid delivery lumen therein. Fluidly coupled to the outlet port
Each of the fluid delivery lumens is fluidly independent of all other fluid delivery lumens of the plurality of fluid delivery members.
With multiple fluid delivery members
A plurality of fluid delivery channels, each of which is fluidly coupled to one or more fluid delivery cavities of the plurality of fluid delivery members.
A fluid delivery mechanism operably coupled to the plurality of fluid delivery channels, wherein the operation of the fluid delivery mechanism is to move the fluid from the plurality of fluid delivery channels to the plurality of fluid delivery members and from the outlet port. A system with a fluid delivery mechanism that allows it to pass out. The operation of the fluid delivery mechanism is claimed to be operably coupled to the plurality of fluid delivery members such that the delivery of the fluid occurs at the same time as the retreat of the fluid delivery member from the extension configuration to the retreat configuration. Item 1. The system according to item 1. The system according to claim 1 or 2, wherein the fluid delivery mechanism comprises a fluid delivery rod. The system according to claim 1, wherein the plurality of fluid delivery members are configured to retract from the extending configuration to the retracting configuration at the same time as fluid delivery from the fluid delivery member. The system according to any one of claims 1-4, wherein the plurality of fluid delivery members are configured to be completely encapsulated in the lumen of the extension member in the retracted configuration. The system according to any one of claims 1-5, wherein the extending member comprises a sheath, a hypotube shaft, or a needle. The system according to any one of claims 1-6, wherein the extending member comprises a metal. The system according to any one of claims 1-7, wherein the extending member comprises a flexible material. The system according to any one of claims 1-8, wherein the extending member includes a rigid material. The system according to any one of claims 1-9, wherein the extending member has a length in the range of about 4 cm to about 250 cm. The system according to claim 10, wherein the extending member has a length in the range of about 4 cm to about 20 cm. The system according to claim 10, wherein the extending member has a length in the range of about 100 cm to about 250 cm. The system according to any one of claims 1-12, wherein the extending member has an outer diameter in the range of about 0.9 mm to about 3.5 mm. 13. The system of claim 13, wherein the extension member has an outer diameter in the range of about 2 mm to about 4 mm. The system according to any one of claims 1-14, wherein the extending member has an outer diameter in the range of about 3 French to about 10 French. The extension member is any of claims 1-15, having an outer diameter sized to fit within the working channel of a conventional biopsy access needle, a conventional endoscope, or a conventional vascular access sheath. Or the system according to item 1. The system according to any one of claims 1-16, wherein the extending member comprises a needle with a gauge number in the range of about 10 to about 20. The system according to any one of claims 1-17, wherein the plurality of fluid delivery members include at least two fluid delivery members. The system of claim 18, wherein the plurality of fluid delivery members comprises 2 to 20 fluid delivery members. The system according to any one of claims 1-19, wherein the plurality of fluid delivery members comprises a plurality of needles or tubes. The system of any one of claims 1-20, wherein the plurality of fluid delivery members comprises a plurality of pencil tip needles, blunt tip needles, or tilted tip needles. The system according to any one of claims 1-21, wherein the plurality of fluid delivery members include metal or plastic. The system according to any one of claims 1-22, wherein the plurality of fluid delivery members include a shape memory alloy. The system according to any one of claims 1-23, wherein the plurality of fluid delivery members include a flexible material. The system according to any one of claims 1-24, wherein the plurality of fluid delivery members include a rigid material. The system according to any one of claims 1-25, wherein each of the plurality of fluid delivery members has an outer diameter in the range of about 0.05 mm to about 0.50 mm. 26. The system of claim 26, wherein each of the plurality of fluid delivery members has an outer diameter of about 0.25 mm. The system according to any one of claims 1-27, wherein each of the plurality of fluid delivery members is a needle with a gauge number of about 28 to about 33. 28. The system of claim 28, wherein each of the plurality of fluid delivery members is a needle with a gauge number of about 31. The system according to any one of claims 1-29, wherein the fluid delivery lumens of the plurality of fluid delivery members each have a volume in the range of about 0.1 μl to about 10 μl. The system according to any one of claims 1-30, wherein each of the plurality of fluid delivery members has a length extending from the distal end of the extension member to the proximal end of the extension member. The system according to any one of claims 1-31, wherein each of the plurality of fluid delivery members has a length in the range of about 4 cm to about 250 cm. One of claims 1-32, each of the plurality of fluid delivery members having a length extending outward from the distal end of the extension member in the extension configuration within a range of about 5 mm to about 40 mm. The system described in the section. The system of any one of claims 1-33, wherein each of the plurality of fluid delivery members comprises at least one additional outlet port fluidly coupled to the fluid delivery lumen. The system according to any one of claims 1-34, wherein in the extending configuration, each of the plurality of fluid delivery members is angled away from the vertical axis of the extending member. 35. The system of claim 35, wherein each of the plurality of fluid delivery members is angled away from the longitudinal axis of the extension member at an angle in the range of about 10 ° to about 90 °. The distal end of the extension member comprises an angular element that guides the plurality of fluid delivery members and is positioned so as to angle away from the longitudinal axis of the extension member in the extension configuration. The system according to any one of 36. In the extension configuration, the extension member is such that the distance between the distal ends of the plurality of fluid delivery members is in the range of about 1 mm to about 10 mm, respectively. The system according to any one of claims 1-37, which is angled away from the vertical axis. The system according to any one of claims 1-38, further comprising a handle adjacent to the proximal end of the extension member. Further comprising an actuator adjacent to the proximal end of the extension member and operably coupled to the plurality of fluid delivery members, the actuation of the actuator can be from the retracted configuration to the extended configuration or from the extended configuration to the said. The system according to any one of claims 1-39, wherein the plurality of fluid delivery members are transferred to a retracted configuration. 40. The actuator is configured to retract the plurality of fluid delivery members from the extended configuration to the retracted configuration at a speed in the range of about 0.1 mm / sec to about 10 mm / sec. system. 40. The system of claim 40, wherein the actuator comprises a mechanical actuator or an electromechanical actuator. 40. The system of claim 40, wherein the actuator is manually operated. 40. The system of claim 40, wherein the actuator is automatically operated. 40. The system of claim 40, wherein the fluid delivery mechanism is actuated by the actuator. The system of any one of claims 1-45, wherein the fluid delivery mechanism comprises a mechanical actuator or an electromechanical actuator. The system of any one of claims 1-46, wherein the fluid delivery mechanism comprises one or more of a plunger or a pump. The system of any one of claims 1-47, wherein the fluid delivery mechanism is manually operated. The system according to any one of claims 1-48, wherein the fluid delivery mechanism is automatically operated. The fluid delivery mechanism is configured to deliver fluid out of the outlet port at a flow rate in the range of about 0.1 μl / sec to about 10 μl / sec, any one of claims 1-49. The system described in. The system according to any one of claims 1-50, wherein the system is configured for fluid delivery from about 1 cm to about 300 cm below the skin surface. 51. The system of claim 51, wherein the system is configured for fluid delivery from about 1 cm to about 30 cm below the skin surface. 51. The system of claim 51, wherein the system is configured for fluid delivery from about 4 cm to about 20 cm below the skin surface. 51. The system of claim 51, wherein the system is configured for fluid delivery from about 100 cm to about 250 cm below the skin surface. The system according to any one of claims 1-54, wherein the plurality of fluid delivery channels comprises fluid delivery lumens of the plurality of fluid delivery members. The system of claim 55, wherein the fluid delivery lumen of the plurality of fluid delivery members is the plurality of fluid delivery channels. The fluid delivery mechanism comprises a plurality of fluid delivery mechanisms, each of which is operably coupled to a single fluid delivery channel of the plurality of fluid delivery channels, claim 1-. The system according to any one of 56. The system according to any one of claims 1-57, further comprising an imaging system for perioperative imaging of the fluid injection system during use. 1-58 of claim 1-58, further comprising one or more cartridges that are fluidly coupled to one or more of the fluid delivery lumens or one or more of the plurality of fluid delivery channels. The system according to any one item. The system according to any one of claims 1-59, wherein each of the plurality of fluid delivery channels has a volume in the range of about 10 μl to about 500 μl. The system according to any one of claims 1-60, further comprising a population of fluorescence tracking microspheres (FTMs). The system of claim 61, wherein the fluorescence tracking microspheres have a diameter of 5 micrometers to 10 micrometers. The system of claim 61 or 62, wherein the fluorescence tracking microspheres comprises polystyrene. The system according to any one of claims 1-63, further comprising a plurality of populations of fluorescence tracking microspheres (FTMs). The system according to any one of claims 1-64, further comprising a volume selector. The system according to any one of claims 1-65, further comprising a plurality of cartridges. A method of injecting fluid into a tumor in the patient's body, the method said.
To provide a fluid infusion system, the fluid infusion system includes an extension member having proximal and distal ends, a plurality of fluid delivery members disposed within the lumen of the extension member, and a plurality of fluid delivery members. It comprises a fluid delivery channel, each of which is fluidly coupled to a single fluid delivery lumen of each of the plurality of fluid delivery members.
Inserting the distal end of the extension member into the body with the plurality of fluid delivery members retracted
Positioning the distal end of the extension member in close proximity to the tumor with the plurality of fluid delivery members retracted.
Extending the plurality of fluid delivery members into the tumor from the distal end of the extension member.
By injecting a plurality of fluids into the tumor from the plurality of fluid delivery members, each of the plurality of fluid delivery members is fluidized from all other of the plurality of fluid delivery members. Independent, including, and methods. 67. The method of claim 67, further comprising retracting the plurality of fluid delivery members from the tumor into the distal end of the extension member. The method of claim 68, wherein retracting the plurality of fluid delivery members occurs in parallel with injecting the plurality of fluids. Retreating the plurality of fluid delivery members comprises retracting the plurality of fluid delivery members so that the plurality of fluid delivery members are completely encapsulated in the lumen of the extension member. Item 68. 28. The method of claim 68, wherein retracting the plurality of fluid delivery members comprises retracting the plurality of fluid delivery members at a speed in the range of about 0.1 mm / sec to about 10 mm / sec. The method of any one of claims 61-71, further comprising removing the distal end of the extension member from the body with the plurality of fluid delivery members retracted. The method of any one of claims 61-72, further comprising excising at least a portion of the tumor for analysis. Any one of claims 61-73, further comprising loading the plurality of fluids into the plurality of fluid delivery channels prior to inserting the distal end of the extension member into the body. The method described in the section. The method of any one of claims 61-74, further comprising imaging the fluid infusion system before and after surgery. The method of any one of claims 61-75, wherein the extension member comprises a sheath, hypotube shaft, or needle. The method according to any one of claims 61-76, wherein the extending member comprises a metal. The method according to any one of claims 61-77, wherein the extending member comprises a flexible material. The method according to any one of claims 61-78, wherein the extending member includes a rigid material. The method according to any one of claims 61-79, wherein the extending member has an outer diameter in the range of about 0.9 mm to about 3.5 mm. The method of any one of claims 61-80, wherein the extending member comprises a needle with a gauge number in the range of about 10 to about 20. Inserting the distal end of the extension member into the body allows the distal end of the extension member to be pre-positioned within the body of a conventional biopsy access needle, conventional endoscope, or. The method of any one of claims 61-81, comprising inserting into the working channel of a conventional vascular access sheath. The method of any one of claims 61-82, wherein the plurality of fluid delivery members comprises at least two fluid delivery members. The method of claim 83, wherein the plurality of fluid delivery members comprises 2 to 20 fluid delivery members. The method of any one of claims 61-84, wherein the plurality of fluid delivery members comprises a plurality of needles or tubes. The method of any one of claims 61-85, wherein the plurality of fluid delivery members comprises metal or plastic. The method according to any one of claims 61-86, wherein the plurality of fluid delivery members include a shape memory alloy. The method of any one of claims 61-87, wherein the plurality of fluid delivery members comprises a flexible material. The method of any one of claims 61-88, wherein the plurality of fluid delivery members comprises a rigid material. The method of any one of claims 61-89, wherein each of the plurality of fluid delivery members has an outer diameter of about 0.05 mm to about 0.50 mm. The method of any one of claims 61-90, wherein each of the plurality of fluid delivery members is a needle with a gauge number of about 28 to about 33. The injection of the plurality of fluids comprises injecting the plurality of fluids at a flow rate in the range of about 0.1 μl / sec to about 10 μl / sec, according to any one of claims 61-91. The method described. The injection of the plurality of fluids comprises injecting a volume in the range of about 10 μl to about 500 μl of each of the plurality of fluids from each of the plurality of fluid delivery members. The method according to any one item. The method of any one of claims 61-93, wherein each of the plurality of fluid delivery members has a length extending from the distal end of the extension member to the proximal end of the extension member. The method of any one of claims 61-94, wherein each of the plurality of fluid delivery members has a length in the range of about 4 cm to about 250 cm. The extension of the plurality of fluid delivery members extends the length of each of the plurality of fluid delivery members in the range of about 5 mm to about 40 mm from the distal end of the extension member into the tumor. The method of any one of claims 61-95, comprising prolonging. The extension of the plurality of fluid delivery members means that the plurality of fluid delivery members are angled away from the vertical axis of the extension member so that the plurality of fluid delivery members are delivered from the distal end of the extension member. The method of any one of claims 61-96, comprising extending the member. 16. The method according to any one of 97. The method of any one of claims 61-98, wherein injecting the plurality of fluids comprises producing a plurality of distinctly different fluid columns within the tumor. The fluid infusion system further comprises a handle having a fluid delivery mechanism on it, the fluid delivery mechanism being operably coupled to the plurality of fluid delivery channels, and injecting the plurality of fluids is said to be the fluid. The method of any one of claims 61-99, comprising activating a delivery mechanism. The method of claim 100, wherein activating the fluid delivery mechanism comprises manually activating the fluid delivery mechanism. The method of claim 100, wherein activating the fluid delivery mechanism comprises automatically activating the fluid delivery mechanism. The method of claim 100, wherein the fluid delivery mechanism comprises a mechanical actuator or an electromechanical actuator. The method of claim 100, wherein the fluid delivery mechanism comprises one or more of a plunger or a pump. The fluid injection system further comprises an actuator that is adjacent to the proximal end of the extension member and operably coupled to the plurality of fluid delivery members, extending the plurality of fluid delivery members. The method of any one of claims 61-104, comprising activating the actuator. The method of claim 105, wherein activating the actuator comprises manually activating the actuator. The method of claim 105, wherein injecting the plurality of fluids comprises actuating the actuator. The method of claim 105, wherein activating the actuator comprises automatically activating the actuator. The method of claim 105, wherein the actuator comprises a mechanical actuator or an electromechanical actuator. 10. The method of claim 105, wherein the actuator comprises one or more of a thumbwheel or an electric actuator. The method according to any one of claims 61-110, wherein injecting the plurality of fluids comprises injecting the plurality of fluids from about 0.2 cm to about 20 cm below the skin surface. The method of claim 111, wherein injecting the plurality of fluids comprises injecting the plurality of fluids from about 1 cm to about 30 cm below the skin surface. The method of claim 111, wherein injecting the plurality of fluids comprises injecting the plurality of fluids from about 4 cm to about 20 cm below the skin surface. The method of claim 111, wherein injecting the plurality of fluids comprises injecting the plurality of fluids from about 100 cm to about 250 cm below the skin surface. The method of any one of claims 61-114, wherein the plurality of fluids comprises one or more therapeutic agents. The method of any one of claims 61-115, wherein injecting the plurality of fluids comprises injecting different fluids into the tumor from each of the plurality of fluid delivery members. The method of any one of claims 61-116, wherein injecting the plurality of fluids comprises injecting the same fluid into the tumor from each of the plurality of fluid delivery members. The tumor is the patient's skin, breast, brain, prostate, colon, rectum, kidney, pancreas, lung, liver, heart, stomach, intestine, ovary, testis, cervix, lymph nodes, thyroid, esophagus, head. Or the method of any one of claims 61-117, located within the cervix, eye, bone, or bladder. The method of any one of claims 61-118, wherein the plurality of fluids comprises a population of fluorescence tracking microspheres (FTMs). The method of any one of claims 67-119, wherein the plurality of fluids comprises a plurality of populations of fluorescence tracking microspheres.

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